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  • 1. Artursson, Karin
    et al.
    Järhult, Josef D
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Olsen, Björn
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Berg, Charlotte
    Varför är det så svårt att förstå betydelsen av One Health?2014In: Svensk veterinärtidning, ISSN 0346-2250, Vol. Feb, no 2, p. 35-39Article in journal (Refereed)
  • 2.
    Atterby, Clara
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Börjesson, Stefan
    Natl Vet Inst SVA, Dept Anim Hlth & Antimicrobial Strategies, Uppsala, Sweden..
    Ny, Sofia
    Publ Hlth Agcy Sweden, Stockholm, Sweden.;Karolinska Inst, Dept Lab Med, Stockholm, Sweden..
    Järhult, Josef D.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Byfors, Sara
    Publ Hlth Agcy Sweden, Stockholm, Sweden..
    Bonnedahl, Jonas
    Linnaeus Univ, Ctr Ecol & Evolut Microbial Model Syst, Kalmar, Sweden.;Kalmar Cty Council, Dept Infect Dis, Kalmar, Sweden.;Linkoping Univ, Dept Clin & Expt Med, Linkoping, Sweden..
    ESBL-producing Escherichia coli in Swedish gulls: A case of environmental pollution from humans?2017In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 12, no 12, article id e0190380Article in journal (Refereed)
    Abstract [en]

    ESBL-producing bacteria are present in wildlife and the environment might serve as a resistance reservoir. Wild gulls have been described as frequent carriers of ESBL-producing E. coli strains with genotypic characteristics similar to strains found in humans. Therefore, potential dissemination of antibiotic resistance genes and bacteria between the human population and wildlife need to be further investigated. Occurrence and characterization of ESBL-producing E. coli in Swedish wild gulls were assessed and compared to isolates from humans, livestock and surface water collected in the same country and similar time-period. Occurrence of ESBL-producing E. coli in Swedish gulls is about three times higher in gulls compared to Swedish community carriers (17% versus 5%) and the genetic characteristics of the ESBL-producing E. coli population in Swedish wild gulls and Swedish human are similar. ESBL-plasmids IncF-and IncI1-type carrying ESBL-genes blaCTX-M-15 or blaCTX-M-14 were most common in isolates from both gulls and humans, but there was limited evidence of clonal transmission. Isolates from Swedish surface water harbored similar genetic characteristics, which highlights surface waters as potential dissemination routes between wildlife and the human population. Even in a low-prevalence country such as Sweden, the occurrence of ESBL producing E. coli in wild gulls and the human population appears to be connected and the occurrence of ESBL-producing E. coli in Swedish gulls is likely a case of environmental pollution.

  • 3.
    Atterby, Clara
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infection medicine.
    Mourkas, Evangelos
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Univ Bath, Dept Biol & Biochem, Milner Ctr Evolut, Bath, Avon, England.
    Meric, Guillaume
    Univ Bath, Dept Biol & Biochem, Milner Ctr Evolut, Bath, Avon, England.
    Pascoe, Ben
    Univ Bath, Dept Biol & Biochem, Milner Ctr Evolut, Bath, Avon, England;MRC CLIMB Consortium, Bath, Avon, England.
    Wang, Helen
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Waldenström, Jonas
    Linnaeus Univ, Ctr Ecol & Evolut Microbial Model Syst, Kalmar, Sweden.
    Sheppard, Samuel K.
    Univ Bath, Dept Biol & Biochem, Milner Ctr Evolut, Bath, Avon, England;MRC CLIMB Consortium, Bath, Avon, England.
    Olsen, Björn
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infection medicine.
    Järhult, Josef D.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infection medicine.
    Ellström, Patrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infection medicine.
    The Potential of Isolation Source to Predict Colonization in Avian Hosts: A Case Study in Campylobacter jejuni Strains From Three Bird Species2018In: Frontiers in Microbiology, ISSN 1664-302X, E-ISSN 1664-302X, Vol. 9, article id 591Article in journal (Refereed)
    Abstract [en]

    Campylobacter jejuni is the primary cause of bacterial gastroenteritis worldwide, infecting humans mostly through consumption of contaminated poultry. C. jejuni is common in the gut of wild birds, and shows distinct strain-specific association to particular bird species. This contrasts with farm animals, in which several genotypes co-exist. It is unclear if the barriers restricting transmission between host species of such specialist strains are related to environmental factors such as contact between host species, bacterial survival in the environment, etc., or rather to strain specific adaptation to the intestinal environment of specific hosts. We compared colonization dynamics in vivo between two host-specific C. jejuni from a song thrush (ST-1304 complex) and a mallard (ST-995), and a generalist strain from chicken (ST-21 complex) in a wild host, the mallard (Anas platyrhynchos). In 18-days infection experiments, the song thrush strain showed only weak colonization and was cleared from all birds after 10 days, whereas both mallard and chicken strains remained stable. When the chicken strain was given 4 days prior to co-infection of the same birds with a mallard strain, it was rapidly outcompeted by the latter. In contrast, when the mallard strain was given 4 days prior to co-infection with the chicken strain, the mallard strain remained and expansion of the chicken strain was delayed. Our results suggest strain-specific differences in the ability of C. jejuni to colonize mallards, likely associated with host origin. This difference might explain observed host association patterns in C. jejuni from wild birds.

  • 4.
    Atterby, Clara
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Nykvist, Marie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Lustig, Ulrika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Andersson, Dan I
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Järhult, Josef D.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Sandegren, Linus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Spread of resistance plasmids and selection of resistant bacteria among Mallards exposed to sub-inhibitory concentrations of antibiotics in their water environmentManuscript (preprint) (Other academic)
  • 5.
    Atterby, Clara
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infection medicine.
    Osbjer, Kristina
    Swedish Univ Agr Sci SLU, Dept Clin Sci, Div Reprod, Uppsala, Sweden; Food & Agr Org United Nations, Phnom Penh, Cambodia.
    Tepper, Viktoria
    Swiss Fed Inst Technol, Inst Environm Engn, Zurich, Switzerland.
    Rajala, Elisabeth
    Swedish Univ Agr Sci SLU, Dept Clin Sci, Div Reprod, Uppsala, Sweden.
    Hernandez, Jorge
    Linnaeus Univ, Ctr Ecol & Evolut Microbial Model Syst, Kalmar, Sweden; Linköping Univ, Kalmar Cty Council, Dept Infect Dis, Dept Clin & Expt Med, Linköping, Sweden; Kalmar Cty Hosp, Diagnost Ctr, Clin Microbiol Lab, Kalmar, Sweden.
    Seng, Sokerya
    Food & Agr Org United Nations, Phnom Penh, Cambodia.
    Holl, Davun
    Minist Agr Forestry & Fisheries, Gen Directorate Anim Hlth & Prod, Phnom Penh, Cambodia.
    Bonnedahl, Jonas
    Linnaeus Univ, Ctr Ecol & Evolut Microbial Model Syst, Kalmar, Sweden; Linköping Univ, Kalmar Cty Council, Dept Infect Dis, Dept Clin & Expt Med, Linköping, Sweden.
    Börjesson, Stefan
    Natl Vet Inst SVA, Dept Anim Hlth & Antimicrobial Strategies, Uppsala, Sweden; Linköping Univ, Dept Clin & Expt Med, Linköping, Sweden.
    Magnusson, Ulf
    Swedish Univ Agr Sci SLU, Dept Clin Sci, Div Reprod, Uppsala, Sweden.
    Järhult, Josef D.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infection medicine.
    Carriage of carbapenemase- and extended-spectrum cephalosporinase-producing Escherichia coli and Klebsiella pneumoniae in humans and livestock in rural Cambodia: gender and age differences and detection of blaOXA-48 in humans2019In: Zoonoses and Public Health, ISSN 1863-1959, E-ISSN 1863-2378, Vol. 66, no 6, p. 603-617Article in journal (Refereed)
    Abstract [en]

    Objectives: This study investigates the frequency and characteristics of carbapenemase‐producing Escherichia coli/Klebsiella pneumoniae (CPE/K) and extended‐spectrum cephalosporinase‐producing E. coli/K. pneumoniae (ESCE/K) in healthy humans and livestock in rural Cambodia. Additionally, household practices as risk factors for faecal carriage of ESCE/K are identified.

    Methods: Faecal samples were obtained from 307 humans and 285 livestock including large ruminants, pigs and poultry living in 100 households in rural Cambodia in 2011. Each household was interviewed, and multilevel logistic model determined associations between household practices/meat consumption and faecal carriage of ESCE/K. CPE and ESCE/K were detected and further screened for colistin resistance genes.

    Results: CPE/K isolates harbouring blaOXA‐48 were identified in two humans. The community carriage of ESCE/K was 20% in humans and 23% in livestock. The same ESBL genes: blaCTX‐M‐15, blaCTX‐M‐14, blaCTX‐M‐27, blaCTX‐M‐55, blaSHV‐2, blaSHV‐12, blaSHV‐28; AmpC genes: blaCMY‐2, blaCMY‐42, blaDHA‐1; and colistin resistance genes: mcr‐1‐like and mcr‐3‐like were detected in humans and livestock. ESCE/K was frequently detected in women, young children, pigs and poultry, which are groups in close contact. The practice of burning or burying meat waste and not collecting animal manure indoors and outdoors daily were identified as risk factors for faecal carriage of ESCE/K.

    Conclusions: Faecal carriage of E. coli and K. pneumoniae harbouring extended‐spectrum cephalosporinase genes are common in the Cambodian community, especially in women and young children. Exposure to animal manure and slaughter products are risk factors for intestinal colonization of ESCE/K in humans.

     

  • 6.
    Atterby, Clara
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Microbiology and Infectious Medicine. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Ramey, Andrew M.
    Gustafsson Hall, Gabriel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Microbiology and Infectious Medicine.
    Järhult, Josef
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Microbiology and Infectious Medicine. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Börjesson, Stefan
    Bonnedahl, Jonas
    Increased prevalence of antibiotic resistant E. coli in gulls sampled in Southcentral Alaska is associated with urban environments2016In: Infection Ecology & Epidemiology, ISSN 2000-8686, E-ISSN 2000-8686, Vol. 6, no 1, article id 32334Article in journal (Refereed)
    Abstract [en]

    Background : Antibiotic-resistant bacteria pose challenges to healthcare delivery systems globally; however, limited information is available regarding the prevalence and spread of such bacteria in the environment. The aim of this study was to compare the prevalence of antibiotic-resistant bacteria in large-bodied gulls ( Larus spp.) at urban and remote locations in Southcentral Alaska to gain inference into the association between antibiotic resistance in wildlife and anthropogenically influenced habitats. Methods : Escherichia coli was cultured ( n 115 isolates) from fecal samples of gulls (n 160) collected from a remote location, Middleton Island, and a more urban setting on the Kenai Peninsula. Results : Screening of E. coli from fecal samples collected from glaucous-winged gulls ( Larus glaucescens )at Middleton Island revealed 8% of isolates were resistant to one or more antibiotics and 2% of the isolates were resistant to three or more antibiotics. In contrast, 55% of E. coli isolates derived from fecal samples collected from large-bodied gulls (i.e. glaucous, herring [ Larus argentatus ], and potentially hybrid gulls) on the Kenai Peninsula were resistant to one or more antibiotics and 22% were resistant to three or more antibiotics. In addition, total of 16% of the gull samples from locations on the Kenai Peninsula harbored extended-spectrum cephalosporin-resistant E. coli isolates (extended-spectrum beta-lactamases [ESBL] and plasmid-encoded AmpC [pAmpC]), in contrast to Middleton Island where no ESBL- or pAmpC-producing isolates were detected. Conclusion : Our findings indicate that increased prevalence of antibiotic resistance is associated with urban environments in Southcentral Alaska and presumably influenced by anthropogenic impacts. Further investigation is warranted to assess how migratory birds may maintain and spread antimicrobial-resistant bacteria of relevance to human and animal health.

  • 7.
    Badrul, Hasan
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Järhult, Josef D.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Absence of vancomycin-resistant enterococci among highly ESBL-positive crows (Corvus splendens) foraging on hospital waste in Bangladesh2015In: Infection Ecology & Epidemiology, ISSN 2000-8686, E-ISSN 2000-8686, Vol. 5, article id 29761Article in journal (Refereed)
    Abstract [en]

    BACKGROUND:

    Vancomycin-resistant enterococci (VRE) have emerged as a growing problem in hospitals; however, domesticated animals, poultry, and wild birds are acting as potential reservoirs. There is a knowledge gap in the Epidemiology of VRE from Bangladesh.

    METHODS:

    To study the prevalence of VRE and the mechanisms of resistance implicated among wild birds, 238 fecal samples were collected in 2010 from house crows (Corvus splendens) foraging on hospital waste in Bangladesh. Fecal samples were screened by analyzing color change in broth and screening for vanA and vanB resistant genes by PCR.

    RESULTS:

    Neither vanA nor vanB genes were detected from the fecal samples. The house crow does not seem to constitute a reservoir for VRE.

    CONCLUSION:

    The zero prevalence is an indication that foraging on hospital waste does not constitute a major risk of VRE carriage in house crows and this is the first study to focus on the prevalence of VRE from wild birds in Bangladesh.

  • 8.
    Blum, Kristin M.
    et al.
    Umea Univ, Dept Chem, S-90187 Umea, Sweden..
    Norström, Sara H.
    Umea Univ, Dept Chem, S-90187 Umea, Sweden..
    Golovko, Oksana
    Univ South Bohemia Ceske Budejovice, Fac Fisheries & Protect Waters, South Bohemian Res Ctr Aquaculture & Biodivers Hy, Zatisi 728-2, Vodnany 38925, Czech Republic..
    Grabic, Roman
    Univ South Bohemia Ceske Budejovice, Fac Fisheries & Protect Waters, South Bohemian Res Ctr Aquaculture & Biodivers Hy, Zatisi 728-2, Vodnany 38925, Czech Republic..
    Järhult, Josef D.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Koba, Olga
    Univ South Bohemia Ceske Budejovice, Fac Fisheries & Protect Waters, South Bohemian Res Ctr Aquaculture & Biodivers Hy, Zatisi 728-2, Vodnany 38925, Czech Republic..
    Söderström Lindström, Hanna
    Umea Univ, Dept Chem, S-90187 Umea, Sweden.;Umea Univ, Dept Publ Hlth & Clin Med, Occupat & Environm Med, S-90187 Umea, Sweden..
    Removal of 30 active pharmaceutical ingredients in surface water under long-term artificial UV irradiation2017In: Chemosphere, ISSN 0045-6535, E-ISSN 1879-1298, Vol. 176, p. 175-182Article in journal (Refereed)
    Abstract [en]

    This study investigated the i) kinetics, and ii) proportion of photolysis of 30 relatively stable active pharmaceutical ingredients (APIs) during artificial UV irradiation for 28 d in ammonium acetate buffer, filtered and unfiltered river water. Buffer was included to control removal kinetics under stable pH conditions and without particulate matter. Dark controls were used to determine removal due to other processes than photolysis and calculate the proportion of photolysis of the total removal. The removal of each API in each matrix was determined using online solid phase extraction/liquid chromatography tandem mass spectrometry (online SPE/LC-MS/MS). Most APIs transformed during the 28 d of UV irradiation and the dark controls showed that photolysis was the major removal process for the majority of the APIs studied. The half-lives ranged from 6 h (amitriptyline) in unfiltered river water to 884 h (37 d, carbamazepine) in buffer. In unfiltered river water, the proportion of APIs with short half-lives (<48 h) was much higher (29%) than in the other matrices (4%), probably due to additional organic carbon, which could have promoted indirect photolysis. Furthermore, two APIs, memantine and fluconazole, were stable in all three matrices, while alprazolam was stable in buffer and unfiltered river water and four additional APIs were stable in buffer. Considering the relatively long-term UV-exposure, this study enabled the investigation of environmentally relevant half-lives in natural waters. Many APIs showed high persistence, which is environmentally concerning and emphasizes the importance of further studies on their environmental fate and effects.

  • 9. Bonnedahl, Jonas
    et al.
    Järhult, Josef D
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Antibiotic resistance in wild birds2014In: Upsala Journal of Medical Sciences, ISSN 0300-9734, E-ISSN 2000-1967, Vol. 119, no 2, p. 113-116Article, review/survey (Refereed)
    Abstract [en]

    Wild birds have been postulated as sentinels, reservoirs, and potential spreaders of antibiotic resistance. Antibiotic-resistant bacteria have been isolated from a multitude of wild bird species. Several studies strongly indicate transmission of resistant bacteria from human rest products to wild birds. There is evidence suggesting that wild birds can spread resistant bacteria through migration and that resistant bacteria can be transmitted from birds to humans and vice versa. Through further studies of the spatial and temporal distribution of resistant bacteria in wild birds, we can better assess their role and thereby help to mitigate the increasing global problem of antibiotic resistance.

  • 10. Bröjer, Caroline
    et al.
    Järhult, Josef D.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Muradrasoli, Shaman
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Virology.
    Söderström, Hanna
    Olsen, Björn
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Gavier-Widén, Dolores
    Pathobiology and virus shedding of low-pathogenic avian influenza virus (A/H1N1) infection in mallards exposed to oseltamivir2013In: Journal of Wildlife Diseases, ISSN 0090-3558, E-ISSN 1943-3700, Vol. 49, no 1, p. 103-113Article in journal (Refereed)
    Abstract [en]

    Low-pathogenic avian influenza (LPAI) viruses in wild birds are important as they can constitute the basis for the development of high-pathogenic avian influenza (HPAI) viruses or form part of human-adapted strains with pandemic potential. However, the LPAI infection as such is not very well characterized in the natural reservoir, dabbling ducks, and results are in part contradictory. The effects on the infection by artificial versus natural infection, exposure to antiviral drugs or development of resistance have not been studied. Therefore, we used q-PCR, histopathology and immunohistochemistry (IHC) to study mallards infected with an influenza A/H1N1 virus isolated from a wild mallard in Sweden. The mallards were either inoculated intra-esophageally or infected by virus shed by other ducks in the experiment. The birds were subjected to low levels of the active metabolite of oseltamivir (Tamiflu®) and the resistance mutation H274Y developed during the course of the experiment.

    All mallards but one had a strictly intestinal localization of the LPAI infection. The exception was a bird euthanized one day post artificial inoculation whose infection was located solely in the lung, possibly due to intra-tracheal deposition of virus. The intestinal infection was characterized by degenerating cells in the lamina propria, infiltrating heterophils and lymphocytes as well as positivity of IHC and q-PCR on samples from feces and intestinal contents. Histopathological changes, IHC positivity and viral shedding all indicate that the infection peaked early, around two days post infection. Furthermore, the infection had a longitudinal progression in the intestine with more activity in the proximal parts early in the infection and vice versa as observed both by IHC and by q-PCR. There was no obvious difference in the course of the infection in artificial versus natural infection, when the level of OC was increased from 80 ng/L to 80 µg/L or when the resistance mutation H274Y developed.

  • 11. Chapman, Joanne R
    et al.
    Helin, Anu S
    Wille, Michelle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Atterby, Clara
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Microbiology and Infectious Medicine.
    Järhult, Josef D
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Fridlund, Jimmy S
    Waldenström, Jonas
    A Panel of Stably Expressed Reference Genes for Real-Time qPCR Gene Expression Studies of Mallards (Anas platyrhynchos)2016In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 11, no 2, article id e0149454Article in journal (Refereed)
    Abstract [en]

    Determining which reference genes have the highest stability, and are therefore appropriate for normalising data, is a crucial step in the design of real-time quantitative PCR (qPCR) gene expression studies. This is particularly warranted in non-model and ecologically important species for which appropriate reference genes are lacking, such as the mallard-a key reservoir of many diseases with relevance for human and livestock health. Previous studies assessing gene expression changes as a consequence of infection in mallards have nearly universally used β-actin and/or GAPDH as reference genes without confirming their suitability as normalisers. The use of reference genes at random, without regard for stability of expression across treatment groups, can result in erroneous interpretation of data. Here, eleven putative reference genes for use in gene expression studies of the mallard were evaluated, across six different tissues, using a low pathogenic avian influenza A virus infection model. Tissue type influenced the selection of reference genes, whereby different genes were stable in blood, spleen, lung, gastrointestinal tract and colon. β-actin and GAPDH generally displayed low stability and are therefore inappropriate reference genes in many cases. The use of different algorithms (GeNorm and NormFinder) affected stability rankings, but for both algorithms it was possible to find a combination of two stable reference genes with which to normalise qPCR data in mallards. These results highlight the importance of validating the choice of normalising reference genes before conducting gene expression studies in ducks. The fact that nearly all previous studies of the influence of pathogen infection on mallard gene expression have used a single, non-validated reference gene is problematic. The toolkit of putative reference genes provided here offers a solid foundation for future studies of gene expression in mallards and other waterfowl.

  • 12.
    El Zowalaty, Mohamed E.
    et al.
    St Jude Childrens Res Hosp, Dept Infect Dis, Lauderdale St, Memphis, TN USA; Univ KwaZulu Natal, Coll Hlth Sci, Sch Hlth Sci, Virol & Microbiol Res Grp, Westville Campus, Durban, South Africa; Univ Sharjah, Sharjah Med Res Inst, Infect Dis & Antiinfect Therapy Res Grp, Sharjah, U Arab Emirates; Univ Sharjah, Coll Pharm, Sharjah, U Arab Emirates.
    Hickman, Rachel A.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Moura, Alexandra
    Inst Pasteur, Natl Reference Ctr, Paris, France; World Hlth Org Collaborating Ctr Listeria, Paris, France; Biol Infect Unit, Inst Pasteur, Paris, France; Inserm, Paris, France.
    Lecuit, Marc
    Inst Pasteur, Natl Reference Ctr, Paris, France; World Hlth Org Collaborating Ctr Listeria, Paris, France; Biol Infect Unit, Inst Pasteur, Paris, France; Inserm U1117, Paris, France; Univ Paris, Inst Imagine, Necker Enfants Malad Univ Hosp, AP HP,Div Infect Dis & Trop Med, Paris, France.
    Zishiri, Oliver T.
    Univ KwaZulu Natal, Coll Agr Engn & Sci, Sch Life Sci, Discipline Genet, Durban, South Africa.
    Noyes, Noelle
    Univ Minnesota, Coll Vet Med, Dept Vet Populat Med, St Paul, MN USA.
    Järhult, Josef D.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Genome Sequence of Listeria innocua Strain MEZLIS26, Isolated from a Goat in South Africa2019In: MICROBIOLOGY RESOURCE ANNOUNCEMENTS, ISSN 2576-098X, Vol. 8, no 44, article id UNSP e00991-19Article in journal (Refereed)
    Abstract [en]

    Here, we report the draft genome sequence of Listeria innocua strain MEZLIS26, isolated from a healthy goat in Flagstaff, Eastern Cape Province, South Africa. The genome was sequenced using the Illumina MiSeq platform and had a length of 2,800,777 bp, with a G+C content of 37.4%, 2,755 coding DNA sequences (CDSs), 49 transfer RNAs (tRNAs), and 4 noncoding RNAs (ncRNAs).

  • 13.
    Eriksson, Hannah K.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Ahadpour, David
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Hailer, Nils
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Lazarinis, Stergios
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Järhult, Josef D.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Linezolid in the treatment of periprosthetic joint infection caused by coagulase-negative staphylococci2019In: Infectious Diseases, ISSN 2374-4235, E-ISSN 2374-4243, Vol. 51, no 9, p. 683-690Article in journal (Refereed)
    Abstract [en]

    Background: Periprosthetic joint infection (PJI) caused by coagulase-negative staphylococci (CoNS) is increasingly common and is sometimes treated with off-label use of linezolid.

    Methods: We conducted a retrospective study of patients with PJI caused by CoNS treated with surgical intervention and orally administrated linezolid during the period 1995-2014 (n = 28). Clinical outcomes and adverse events related to linezolid administration were evaluated. Mean time to follow-up was 4.3 years (range: 0.2-12).

    Results: Twenty-two of 28 patients were infection-free at follow-up. No CoNS strain was resistant to vancomycin, but 16 of 28 were resistant to rifampicin, 23 of 28 to clindamycin and 20 of 27 to quinolones. The mean duration of linezolid treatment was 4.2 weeks (range: 1-12). Eleven of 28 patients had an adverse event related to the antimicrobial treatment, and four had to discontinue linezolid, but all adverse events were reversible within 2 months after discontinuation.

    Conclusions: Oral linezolid administration combined with adequate surgical treatment may be useful for the treatment of PJIs caused by CoNS.

  • 14.
    Eriksson, Per
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Lindskog, Cecilia
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology.
    Lorente-Leal, Victor
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Waldenström, Jonas
    Linnaeus Univ, Ctr Ecol & Evolut Microbial Model Syst, Kalmar, Sweden.
    González-Acuna, Daniel
    Univ Concepcion, Fac Ciencias Vet, Chillan, Chile.
    Järhult, Josef D.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infection medicine.
    Lundkvist, Åke
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Olsen, Björn
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infection medicine.
    Jourdain, Elsa
    INRA, UMR0346 EPIA, VetAgro Sup, St Genes Champanelle, France.
    Ellström, Patrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infection medicine.
    Attachment Patterns of Human and Avian Influenza Viruses to Trachea and Colon of 26 Bird Species: Support for the Community Concept2019In: Frontiers in Microbiology, ISSN 1664-302X, E-ISSN 1664-302X, Vol. 10, article id 815Article in journal (Refereed)
    Abstract [en]

    Avian influenza A viruses (AIVs) have a broad host range, but are most intimately associated with waterfowl (Anseriformes) and, in the case of the H13 and H16 subtypes, gulls (Charadriiformes). Host associations are multifactorial, but a key factor is the ability of the virus to bind host cell receptors and thereby initiate infection. The current study aims at investigating the tissue attachment pattern of a panel of AIVs, comprising H3N2, H6N1, H12N5, and H16N3, to avian trachea and colon tissue samples obtained from host species of different orders. Virus attachment was not restricted to the bird species or order from which the virus was isolated. Instead, extensive virus attachment was observed to several distantly related avian species. In general, more virus attachment and receptor expression were observed in trachea than in colon samples. Additionally, a human seasonal H3N2 virus was studied. Unlike the studied AIVs, this virus mainly attached to tracheae from Charadriiformes and a very limited set of avian cola. In conclusion, the reported results highlight the importance of AIV attachment to trachea in many avian species. Finally, the importance of chickens and mallards in AIVs dynamics was illustrated by the abundant AIV attachment observed.

  • 15.
    Fedorova, Ganna
    et al.
    Umea Univ, Dept Chem, SE-90187 Umea, Sweden; Univ South Bohemia Ceske Budejovice, Fac Fisheries & Protect Waters, South Bohemian Res Ctr Aquaculture & Biodivers Hy, Zatisi 728-2, Vodnany 38925, Czech Republic .
    Grabic, Roman
    Univ South Bohemia Ceske Budejovice, Fac Fisheries & Protect Waters, South Bohemian Res Ctr Aquaculture & Biodivers Hy, Zatisi 728-2, Vodnany 38925, Czech Republic.
    Nyhlen, Jonas
    Ozone Tech Syst OTS AB, SE-12630 Hagersten, Sweden.
    Järhult, Josef D.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Söderström, Hanna
    Umea Univ, Dept Chem, SE-90187 Umea, Sweden.
    Fate of three anti-influenza drugs during ozonation of wastewater effluents - degradation and formation of transformation products.2016In: Chemosphere, ISSN 0045-6535, E-ISSN 1879-1298, Vol. 150, p. 723-730Article in journal (Refereed)
    Abstract [en]

    Anti-influenza drugs constitute a key component of pandemic preparedness plans against influenza. However, the occurrence of such drugs in water environments, the potential of resistance development in the natural hosts, and the risk for transmission of antiviral resistance to humans call for measures to increase removal in wastewater treatment plants (WWTPs). In this study, removal of three anti-influenza drugs; amantadine (AM), oseltamivir carboxylate (OC) and zanamivir (ZA), and formation/removal of their transformation products during ozonation of wastewater effluents from two Swedish WWTPs in Uppsala and Stockholm were studied. The removal profile of target antivirals and formation/removal of their transformation products were studied by liquid chromatography/high resolution mass spectrometry. 3.5 h of ozone exposure (total dose of ozone 5.95 g) led to complete removal of the three anti-influenza drugs with a degradation in the following order ZA > OC > AM. Two, five and one transformation products were identified and semi-quantified for AM, OC and ZA, respectively. Increasing and later decreasing transformation products concentration followed the decrease in concentration of target compounds. All transformation products detected, except one of AM in wastewater from Stockholm WWTP, were removed at the end of the experiment. The removal efficiency was higher for all studied compounds in wastewater from Uppsala WWTP, which had lower TOC and COD values, less phosphorus, and also higher pH in the water. Ozonation thus offers multiple benefits through its potential to degrade influenza antivirals, hence decrease the risk of environmental resistance development, in addition to degrading other pharmaceuticals and resistant microorganisms.

  • 16.
    Gillman, Anna
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Muradrasoli, Shaman
    Mårdnäs, Andreas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Söderström, Hanna
    Fedorova, Ganna
    Löwenthal, Max
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Wille, Michelle
    Daggfeldt, Annika
    Järhult, Josef D
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Oseltamivir Resistance in Influenza A(H6N2) Caused by an R292K Substitution in Neuraminidase Is Not Maintained in Mallards without Drug Pressure.2015In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 10, no 9Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Wild waterfowl is the natural reservoir of influenza A virus (IAV); hosted viruses are very variable and provide a source for genetic segments which can reassort with poultry or mammalian adapted IAVs to generate novel species crossing viruses. Additionally, wild waterfowl act as a reservoir for highly pathogenic IAVs. Exposure of wild birds to the antiviral drug oseltamivir may occur in the environment as its active metabolite can be released from sewage treatment plants to river water. Resistance to oseltamivir, or to other neuraminidase inhibitors (NAIs), in IAVs of wild waterfowl has not been extensively studied.

    AIM AND METHODS: In a previous in vivo Mallard experiment, an influenza A(H6N2) virus developed oseltamivir resistance by the R292K substitution in the neuraminidase (NA), when the birds were exposed to oseltamivir. In this study we tested if the resistance could be maintained in Mallards without drug exposure. Three variants of resistant H6N2/R292K virus were each propagated during 17 days in five successive pairs of naïve Mallards, while oseltamivir exposure was decreased and removed. Daily fecal samples were analyzed for viral presence, genotype and phenotype.

    RESULTS AND CONCLUSION: Within three days without drug exposure no resistant viruses could be detected by NA sequencing, which was confirmed by functional NAI sensitivity testing. We conclude that this resistant N2 virus could not compete in fitness with wild type subpopulations without oseltamivir drug pressure, and thus has no potential to circulate among wild birds. The results of this study contrast to previous observations of drug induced resistance in an avian H1N1 virus, which was maintained also without drug exposure in Mallards. Experimental observations on persistence of NAI resistance in avian IAVs resemble NAI resistance seen in human IAVs, in which resistant N2 subtypes do not circulate, while N1 subtypes with permissive mutations can circulate without drug pressure. We speculate that the phylogenetic group N1 NAs may easier compensate for NAI resistance than group N2 NAs, though further studies are needed to confirm such conclusions.

  • 17.
    Gillman, Anna
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Microbiology and Infectious Medicine. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Muradrasoli, Shaman
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Soderstrom, Hanna
    Holmberg, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Latorre-Margalef, Neus
    Tolf, Conny
    Waldenstrom, Jonas
    Gunnarsson, Gunnar
    Olsen, Björn
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Microbiology and Infectious Medicine. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Järhult, Josef D.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Oseltamivir-Resistant Influenza A (H1N1) Virus Strain with an H274Y Mutation in Neuraminidase Persists without Drug Pressure in Infected Mallards2015In: Applied and Environmental Microbiology, ISSN 0099-2240, E-ISSN 1098-5336, Vol. 81, no 7, p. 2378-2383Article in journal (Refereed)
    Abstract [en]

    Influenza A virus (IAV) has its natural reservoir in wild waterfowl, and emerging human IAVs often contain gene segments from avian viruses. The active drug metabolite of oseltamivir (oseltamivir carboxylate [OC]), stockpiled as Tamiflu for influenza pandemic preparedness, is not removed by conventional sewage treatment and has been detected in river water. There, it may exert evolutionary pressure on avian IAV in waterfowl, resulting in the development of resistant viral variants. A resistant avian IAV can circulate among wild birds only if resistance does not restrict viral fitness and if the resistant virus can persist without continuous drug pressure. In this in vivo mallard (Anas platyrhynchos) study, we tested whether an OC-resistant avian IAV (H1N1) strain with an H274Y mutation in the neuraminidase (NA-H274Y) could retain resistance while drug pressure was gradually removed. Successively infected mallards were exposed to decreasing levels of OC, and fecal samples were analyzed for the neuraminidase sequence and phenotypic resistance. No reversion to wild-type virus was observed during the experiment, which included 17 days of viral transmission among 10 ducks exposed to OC concentrations below resistance induction levels. We conclude that resistance in avian IAV that is induced by exposure of the natural host to OC can persist in the absence of the drug. Thus, there is a risk that human-pathogenic IAVs that evolve from IAVs circulating among wild birds may contain resistance mutations. An oseltamivir-resistant pandemic IAV would pose a substantial public health threat. Therefore, our observations underscore the need for prudent oseltamivir use, upgraded sewage treatment, and surveillance for resistant IAVs in wild birds.

  • 18.
    Gillman, Anna
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Muradrasoli, Shaman
    Söderström, Hanna
    Nordh, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Bröjer, Caroline
    Lindberg, Richard H
    Latorre-Margalef, Neus
    Waldenström, Jonas
    Olsen, Björn
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Järhult, Josef D
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Resistance Mutation R292K Is Induced in Influenza A(H6N2) Virus by Exposure of Infected Mallards to Low Levels of Oseltamivir2013In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 8, no 8, p. e71230-Article in journal (Refereed)
    Abstract [en]

    Resistance to neuraminidase inhibitors (NAIs) is problematic as these drugs constitute the major treatment option for severe influenza. Extensive use of the NAI oseltamivir (Tamiflu®) results in up to 865 ng/L of its active metabolite oseltamivir carboxylate (OC) in river water. There one of the natural reservoirs of influenza A, dabbling ducks, can be exposed. We previously demonstrated that an influenza A(H1N1) virus in mallards (Anas platyrhynchos) exposed to 1 µg/L of OC developed oseltamivir resistance through the mutation H274Y (N2-numbering). In this study, we assessed the resistance development in an A(H6N2) virus, which belongs to the phylogenetic N2 group of neuraminidases with distinct functional and resistance characteristics. Mallards were infected with A(H6N2) while exposed to 120 ng/L, 1.2 µg/L or 12 µg/L of OC in their sole water source. After 4 days with 12 µg/L of OC exposure, the resistance mutation R292K emerged and then persisted. Drug sensitivity was decreased ≈13,000-fold for OC and ≈7.8-fold for zanamivir. Viral shedding was similar when comparing R292K and wild-type virus indicating sustained replication and transmission. Reduced neuraminidase activity and decrease in recovered virus after propagation in embryonated hen eggs was observed in R292K viruses. The initial, but not the later R292K isolates reverted to wild-type during egg-propagation, suggesting a stabilization of the mutation, possibly through additional mutations in the neuraminidase (D113N or D141N) or hemagglutinin (E216K). Our results indicate a risk for OC resistance development also in a N2 group influenza virus and that exposure to one NAI can result in a decreased sensitivity to other NAIs as well. If established in influenza viruses circulating among wild birds, the resistance could spread to humans via re-assortment or direct transmission. This could potentially cause an oseltamivir-resistant pandemic; a serious health concern as preparedness plans rely heavily on oseltamivir before vaccines can be mass-produced.

  • 19.
    Gillman, Anna
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Nykvist, Marie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Muradrasoli, Shaman
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Söderström, Hanna
    Wille, Michelle
    Daggfeldt, Annika
    Bröjer, Caroline
    Waldenström, Jonas
    Olsen, Björn
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Järhult, Josef D
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Influenza A(H7N9) Virus Acquires Resistance-Related Neuraminidase I222T Substitution When Infected Mallards Are Exposed to Low Levels of Oseltamivir in Water2015In: Antimicrobial Agents and Chemotherapy, ISSN 0066-4804, E-ISSN 1098-6596, Vol. 59, no 9, p. 5196-5202Article in journal (Refereed)
    Abstract [en]

    Influenza A virus (IAV) has its natural reservoir in wild waterfowl, and new human IAVs often contain gene segments originating from avian IAVs. Treatment options for severe human influenza are principally restricted to neuraminidase inhibitors (NAIs), among which oseltamivir is stockpiled in preparedness for influenza pandemics. There is evolutionary pressure in the environment for resistance development to oseltamivir in avian IAVs, as the active metabolite oseltamivir carboxylate (OC) passes largely undegraded through sewage treatment to river water where waterfowl reside. In an in vivo mallard (Anas platyrhynchos) model, we tested if low-pathogenic avian influenza A(H7N9) virus might become resistant if the host was exposed to low levels of OC. Ducks were experimentally infected, and OC was added to their water, after which infection and transmission were maintained by successive introductions of uninfected birds. Daily fecal samples were tested for IAV excretion, genotype, and phenotype. Following mallard exposure to 2.5 μg/liter OC, the resistance-related neuraminidase (NA) I222T substitution, was detected within 2 days during the first passage and was found in all viruses sequenced from subsequently introduced ducks. The substitution generated 8-fold and 2.4-fold increases in the 50% inhibitory concentration (IC50) for OC (P < 0.001) and zanamivir (P = 0.016), respectively. We conclude that OC exposure of IAV hosts, in the same concentration magnitude as found in the environment, may result in amino acid substitutions, leading to changed antiviral sensitivity in an IAV subtype that can be highly pathogenic to humans. Prudent use of oseltamivir and resistance surveillance of IAVs in wild birds are warranted.

  • 20. Hailer, NP
    et al.
    Järhult, Josef D
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Nitsch, R
    Resting Microglial Cells in Vitro: Analysis of Morphology and Adhesion Molecule Expression in Organotypic Hippocampal Slice Cultures.1996In: Glia, ISSN 0894-1491, E-ISSN 1098-1136, Vol. 18, no 4, p. 319-31Article in journal (Refereed)
  • 21.
    Hasan, Badrul
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Laurell, Karl
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Rakib, Mufti Mahmud
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Ahlstedt, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Hernandez, Jorge
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases. Linnaeus Univ, Sch Nat Sci, Kalmar, Sweden.;Kalmar Cty Hosp, Clin Microbiol, Kalmar, Sweden..
    Caceres, Mercedes
    Natl Autonomous Univ Leon UNAN Leon, Fac Med Sci, Dept Microbiol, Leon, Nicaragua..
    Järhult, Josef D.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Fecal Carriage of Extended-Spectrum -Lactamases in Healthy Humans, Poultry, and Wild Birds in Leon, NicaraguaA Shared Pool of bla(CTX-M) Genes and Possible Interspecies Clonal Spread of Extended-Spectrum -Lactamases-Producing Escherichia coli2016In: Microbial Drug Resistance, ISSN 1076-6294, E-ISSN 1931-8448, Vol. 22, no 8, p. 682-687Article in journal (Refereed)
    Abstract [en]

    Antibiotic-resistant bacteria are a major concern in the healthcare of today, especially the increasing number of gram-negative bacteria producing -lactamases such as extended-spectrum -lactamases (ESBLs). However, little is known about the relationship of ESBL producers in humans and domestic and wild birds, especially in a low-income setting. Therefore, we studied the fecal carriage of ESBL-producing Escherichia coli and Klebsiella pneumoniae in healthy humans, poultry, and wild birds in the vicinity of Leon, Nicaragua. Three hundred fecal samples were collected during December 2012 from humans (n=100), poultry (n=100) and wild birds (n=100). The samples were examined for ESBL-producing E. coli and K. pneumoniae, revealing the prevalence of 27% in humans, 13% in poultry, and 8% in wild birds. Further characterization of the ESBL-producing isolates was performed through polymerase chain reaction (PCR) (NDM, CTX-M), epidemiological typing (ERIC2-PCR), multilocus sequence typing, and sequencing. ESBL producers harbored bla(CTX-M-2), bla(CTX-M-15), bla(CTX-M-22), and bla(CTX-M-3) genotypes. The bla(CTX-M-15) constituted the absolute majority of ESBL genes among all samples. ERIC-PCR demonstrated highly related E. coli clones among humans, poultry, and wild birds. Clinically relevant E. coli clone ST648 was found in humans and poultry. There is a shared pool of bla(CTX-M) genes between humans and domesticated and wild birds in Nicaragua, and the results suggest shared clones of ESBL-producing E. coli. The study adds to the notion that wild birds and poultry can pick up antibiotic-resistant bacteria of human origin and function as a melting pot of resistance. Structured surveillance programs of antimicrobial resistance and a more regulated prescription of antibiotics are warranted in Nicaragua.

  • 22.
    Helin, Anu S
    et al.
    Centre for Ecology and Evolution in Microbial Model Systems, Linnaeus University, Kalmar, Sweden.
    Wille, Michelle
    Centre for Ecology and Evolution in Microbial Model Systems, Linnaeus University, Kalmar, Sweden.
    Atterby, Clara
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infection medicine.
    Järhult, Josef D.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Waldenström, Jonas
    Centre for Ecology and Evolution in Microbial Model Systems, Linnaeus University, Kalmar, Sweden.
    Chapman, Joanne R.
    Centre for Ecology and Evolution in Microbial Model Systems, Linnaeus University, Kalmar, Sweden; Department of Molecular Biosciences, University of Kansas, Lawrence, USA.
    A rapid and transient innate immune response to avian influenza infection in mallards2018In: Molecular Immunology, ISSN 0161-5890, E-ISSN 1872-9142, Vol. 95, p. 64-72Article in journal (Refereed)
    Abstract [en]

    The vertebrate innate immune system provides hosts with a rapid, non-specific response to a wide range of invading pathogens. However, the speed and duration of innate responses will be influenced by the co-evolutionary dynamics of specific host-pathogen combinations. Here, we show that low pathogenic avian influenza virus (LPAI) subtype H1N1 elicits a strong but extremely transient innate immune response in its main wildlife reservoir, the mallard (Anas platyrhynchos). Using a series of experimental and methodological improvements over previous studies, we followed the expression of retinoic acid inducible gene 1 (RIG-I) and myxovirus resistance gene (Mx) in mallards semi-naturally infected with low pathogenic H1N1. One day post infection, both RIG-I and Mx were significantly upregulated in all investigated tissues. By two days post infection, the expression of both genes had generally returned to basal levels, and remained so for the remainder of the experiment. This is despite the fact that birds continued to actively shed viral particles throughout the study period. We additionally show that the spleen plays a particularly active role in the innate immune response to LPAI. Waterfowl and avian influenza viruses have a long co-evolutionary history, suggesting that the mallard innate immune response has evolved to provide a minimum effective response to LPAIs such that the viral infection is brought under control while minimising the damaging effects of a sustained immune response.

  • 23. Helin, AS
    et al.
    Wille, M
    Atterby, Clara
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Järhult, Josef D.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Waldenström, J
    Chapman, JR
    Expression of immune genes RIG-I and Mx in mallard ducks infected with low pathogenic avian influenza (LPAI):: A dataset.2018In: Data in Brief, E-ISSN 2352-3409, Vol. 18, p. 1562-1566Article in journal (Refereed)
    Abstract [en]

    This article provides data on primer sequences used to amplify the innate immune genes RIG-I and Mx and a set of normalizing reference genes in mallards (Anas platyrhynchos), and shows which reference genes are stable, per tissue, for our experimental settings. Data on the expressional changes of these two genes over a time-course of infection with low pathogenic avian influenza virus (LPAI) are provided. Individual-level data are also presented, including LPAI infection load, and per tissue gene expression of RIG-I and Mx. Gene expression in two outlier individuals is explored in more depth.

  • 24.
    Hessman, Jon
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Atterby, Clara
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Olsen, Björn
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Järhult, Josef D.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    High Prevalence and Temporal Variation of Extended Spectrum β-Lactamase–Producing Bacteria in Urban Swedish Mallards2018In: Microbial Drug Resistance, ISSN 1076-6294, E-ISSN 1931-8448Article in journal (Refereed)
    Abstract [en]

    Antibiotic resistant bacteria present a growing global healthcare challenge. Previous research demonstrates that wild birds harbor extended spectrum -lactamase (ESBL)-producing Enterobacteriaceae and may contribute to their dissemination. We aimed to assess prevalence and temporal variation in the detection rate of ESBL-producing bacteria in urban wild birds and to evaluate methods regarding sample handling. Monthly fecal sampling was performed in 2013 at an urban pond in Sweden. ESBL-producing Escherichia coli and Klebsiella pneumoniae were analyzed by polymerase chain reaction targeting bla(CTX-M). Subsets of samples were analyzed in multiple replicates and without previous freezing. Pond water samples were screened for 12 antibiotics. Out of 813 fecal samples, 47% grew ESBL-producing E. coli, a higher prevalence than in similar studies. Detection rate varied considerably between months, ranging from 4.2% in May to 84% in July, and was significantly higher during warm months. A majority of isolates harbored CTX-M-15 type ESBL. Detection rates were increased by duplicating samples and by avoiding freezing. No antibiotics were detected in pond water. This study demonstrates high prevalence and a previously undescribed temporal variation in detection rate of ESBL-producing Enterobacteriaceae in wild birds. The distribution of CTX-M genes corresponds well with Swedish human isolates, indicating communication between the genetic pools of ESBLs in humans and wild birds. Urban ponds may serve as important natural reservoirs for antimicrobial resistance.

  • 25.
    Järhult, Josef D.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Environmental resistance development to influenza antivirals: a case exemplifying the need for a multidisciplinary One Health approach including physicians2018In: Acta veterinaria Scandinavica, ISSN 0044-605X, Vol. 60, article id 6Article, review/survey (Refereed)
    Abstract [en]

    A multidisciplinary approach is a prerequisite for One Health. Physicians are important players in the One Health team, yet they are often hard to convince of the benefits of the One Health approach. Here, the case for multidisciplinarity including physicians is made using the example of environmental resistance development to influenza antivirals. Neuraminidase inhibitors are the major class of anti-influenza pharmaceuticals, and extensively stockpiled globally as a cornerstone of pandemic preparedness, especially important in the first phase before vaccines can be mass-produced. The active metabolite of oseltamivir that is excreted from treated patients degrades poorly in conventional sewage treatment processes and has been found in river waters. Dabbling ducks constitute the natural influenza A virus reservoir and often reside near sewage treatment plant outlets, where they may be exposed to neuraminidase inhibitor residues. In vivo experiments using influenza-infected Mallards exposed to neuraminidase inhibitors present in their water have shown resistance development and persistence, demonstrating that resistance may be induced and become established in the influenza strains circulating in natural hosts. Neuraminidase inhibitor resistance genes may become part of a human-adapted influenza virus with pandemic potential through reassortment or direct transmission. A pandemic caused by a neuraminidase inhibitor-resistant influenza virus is a serious threat as the first line defense in pandemic preparedness would be disarmed. To assess the risk for environmental influenza resistance development, a broad multidisciplinary team containing chemists, social scientists, veterinarians, biologists, ecologists, virologists, epidemiologists, and physicians is needed. Information about One Health early in high school and undergraduate training, an active participation of One Health-engaged physicians in the debate, and more One Health-adapted funding and publication possibilities are suggested to increase the possibility to engage physicians.

  • 26.
    Järhult, Josef D.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    One Health: a doctor's perspective2015In: The Veterinary Record, ISSN 0042-4900, E-ISSN 2042-7670, Vol. 176, no 14, p. 351-353Article in journal (Refereed)
  • 27.
    Järhult, Josef D
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Oseltamivir (Tamiflu(®)) in the environment, resistance development in influenza A viruses of dabbling ducks and the risk of transmission of an oseltamivir-resistant virus to humans: a review2012In: Infection ecology & epidemiology, ISSN 2000-8686, Vol. 2, p. 18385-Article in journal (Refereed)
    Abstract [en]

    The antiviral drug oseltamivir (Tamiflu(®)) is a cornerstone in influenza pandemic preparedness plans worldwide. However, resistance to the drug is a growing concern. The active metabolite oseltamivir carboxylate (OC) is not degraded in surface water or sewage treatment plants and has been detected in river water during seasonal influenza outbreaks. The natural influenza reservoir, dabbling ducks, can thus be exposed to OC in aquatic environments. Environmental-like levels of OC induce resistance development in influenza A/H1N1 virus in mallards. There is a risk of resistance accumulation in influenza viruses circulating among wild birds when oseltamivir is used extensively. By reassortment or direct transmission, oseltamivir resistance can be transmitted to humans potentially causing a resistant pandemic or human-adapted highly-pathogenic avian influenza virus. There is a need for more research on resistance development in the natural influenza reservoir and for a prudent use of antivirals.

  • 28.
    Järhult, Josef D.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Tamiflu® - Use It and Lose It?2011Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Influenza A viruses cause seasonal and pandemic outbreaks that range from mild infections to the disastrous Spanish Flu. Resistance to neuraminidase inhibitors (NAIs) is a growing problem as these drugs constitute a vital part of treatment strategies and pandemic preparedness plans worldwide. Oseltamivir (Tamiflu®) is the mostly used NAI. Its active metabolite, oseltamivir carboxylate (OC), is excreted from treated patients and degrades poorly in sewage treatment plants and surface water. Thus, OC can enter aquatic environments where the natural influenza reservoir, dabbling ducks, can be exposed to the substance and resistance could develop. If NAI resistance is established in influenza viruses circulating among wild birds, the resistance can form part of a virus re-entering the human population either by reassortment or by direct transmission.

    In this thesis, evidence is presented that OC is present in the waterways during a seasonal influenza outbreak in Japan, a country in which oseltamivir is liberally used. Furthermore, when mallards were infected with an influenza A/H1N1 virus and subjected to low, environmental-like concentrations of OC, resistance developed through acquisition of the well-known resistance mutation H274Y. The influenza infection in the mallards was mainly intestinal, had a rapid onset and was progressing in a longitudinal fashion in the intestine. Finally, influenza A viruses isolated from wild mallards in Sweden and containing resistance-related mutations were examined by a neuraminidase inhibition assay. The viruses did not have a decreased sensitivity to NAIs, but had mutations with a resistance-enhancing potential.

    Thus, OC is present in the environment and environmental-like concentrations of OC induce resistance in influenza viruses of dabbling ducks. The present resistance situation among wild birds is not well understood but the existence of H274Y among wild birds, though rare, and the spread of the former seasonal A/H1N1 virus containing H274Y among humans indicate that resistance mutations could establish themselves also among wild birds. An oseltamivir-resistant pandemic or a human-adapted highly-pathogenic avian influenza virus are frightening scenarios as oseltamivir is a cornerstone in the defense in those situations. There is a need for further studies, surveillance in wild birds and for a prudent use of antivirals.

    List of papers
    1. Detection of the antiviral drug oseltamivir in aquatic environments
    Open this publication in new window or tab >>Detection of the antiviral drug oseltamivir in aquatic environments
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    2009 (English)In: PloS one, ISSN 1932-6203, Vol. 4, no 6, p. e6064-Article in journal (Refereed) Published
    Abstract [en]

    Oseltamivir (Tamiflu) is the most important antiviral drug available and a cornerstone in the defence against a future influenza pandemic. Recent publications have shown that the active metabolite, oseltamivir carboxylate (OC), is not degraded in sewage treatment plants and is also persistent in aquatic environments. This implies that OC will be present in aquatic environments in areas where oseltamivir is prescribed to patients for therapeutic use. The country where oseltamivir is used most is Japan, where it is used to treat seasonal flu. We measured the levels of OC in water samples from the Yodo River system in the Kyoto and Osaka prefectures, Japan, taken before and during the flu-season 2007/8. No OC was detected before the flu-season but 2-58 ng L(-1) was detected in the samples taken during the flu season. This study shows, for the first time, that low levels of oseltamivir can be found in the aquatic environment. Therefore the natural reservoir of influenza virus, dabbling ducks, is exposed to oseltamivir, which could promote the evolution of viral resistance.

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-113800 (URN)10.1371/journal.pone.0006064 (DOI)000267424600012 ()19557131 (PubMedID)
    Available from: 2010-02-04 Created: 2010-02-04 Last updated: 2012-01-03Bibliographically approved
    2. Environmental Levels of the Antiviral Oseltamivir Induce Development of Resistance Mutation H274Y in Influenza A/H1N1 Virus in Mallards
    Open this publication in new window or tab >>Environmental Levels of the Antiviral Oseltamivir Induce Development of Resistance Mutation H274Y in Influenza A/H1N1 Virus in Mallards
    Show others...
    2011 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 6, no 9, p. e24742-Article in journal (Refereed) Published
    Abstract [en]

    Oseltamivir (Tamiflu (R)) is the most widely used drug against influenza infections and is extensively stockpiled worldwide as part of pandemic preparedness plans. However, resistance is a growing problem and in 2008-2009, seasonal human influenza A/H1N1 virus strains in most parts of the world carried the mutation H274Y in the neuraminidase gene which causes resistance to the drug. The active metabolite of oseltamivir, oseltamivir carboxylate (OC), is poorly degraded in sewage treatment plants and surface water and has been detected in aquatic environments where the natural influenza reservoir, dabbling ducks, can be exposed to the substance. To assess if resistance can develop under these circumstances, we infected mallards with influenza A/H1N1 virus and exposed the birds to 80 ng/L, 1 mu g/L and 80 mu g/L of OC through their sole water source. By sequencing the neuraminidase gene from fecal samples, we found that H274Y occurred at 1 mu g/L of OC and rapidly dominated the viral population at 80 mu g/L. IC(50) for OC was increased from 2-4 nM in wild-type viruses to 400-700 nM in H274Y mutants as measured by a neuraminidase inhibition assay. This is consistent with the decrease in sensitivity to OC that has been noted among human clinical isolates carrying H274Y. Environmental OC levels have been measured to 58-293 ng/L during seasonal outbreaks and are expected to reach mu g/L-levels during pandemics. Thus, resistance could be induced in influenza viruses circulating among wild ducks. As influenza viruses can cross species barriers, oseltamivir resistance could spread to human-adapted strains with pandemic potential disabling oseltamivir, a cornerstone in pandemic preparedness planning. We propose surveillance in wild birds as a measure to understand the resistance situation in nature and to monitor it over time. Strategies to lower environmental levels of OC include improved sewage treatment and, more importantly, a prudent use of antivirals.

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-159471 (URN)10.1371/journal.pone.0024742 (DOI)000294803200047 ()
    Available from: 2011-10-04 Created: 2011-10-03 Last updated: 2017-12-08Bibliographically approved
    3. Pathobiology and virus shedding of low-pathogenic avian influenza virus (A/H1N1) infection in mallards exposed to oseltamivir
    Open this publication in new window or tab >>Pathobiology and virus shedding of low-pathogenic avian influenza virus (A/H1N1) infection in mallards exposed to oseltamivir
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    2013 (English)In: Journal of Wildlife Diseases, ISSN 0090-3558, E-ISSN 1943-3700, Vol. 49, no 1, p. 103-113Article in journal (Refereed) Published
    Abstract [en]

    Low-pathogenic avian influenza (LPAI) viruses in wild birds are important as they can constitute the basis for the development of high-pathogenic avian influenza (HPAI) viruses or form part of human-adapted strains with pandemic potential. However, the LPAI infection as such is not very well characterized in the natural reservoir, dabbling ducks, and results are in part contradictory. The effects on the infection by artificial versus natural infection, exposure to antiviral drugs or development of resistance have not been studied. Therefore, we used q-PCR, histopathology and immunohistochemistry (IHC) to study mallards infected with an influenza A/H1N1 virus isolated from a wild mallard in Sweden. The mallards were either inoculated intra-esophageally or infected by virus shed by other ducks in the experiment. The birds were subjected to low levels of the active metabolite of oseltamivir (Tamiflu®) and the resistance mutation H274Y developed during the course of the experiment.

    All mallards but one had a strictly intestinal localization of the LPAI infection. The exception was a bird euthanized one day post artificial inoculation whose infection was located solely in the lung, possibly due to intra-tracheal deposition of virus. The intestinal infection was characterized by degenerating cells in the lamina propria, infiltrating heterophils and lymphocytes as well as positivity of IHC and q-PCR on samples from feces and intestinal contents. Histopathological changes, IHC positivity and viral shedding all indicate that the infection peaked early, around two days post infection. Furthermore, the infection had a longitudinal progression in the intestine with more activity in the proximal parts early in the infection and vice versa as observed both by IHC and by q-PCR. There was no obvious difference in the course of the infection in artificial versus natural infection, when the level of OC was increased from 80 ng/L to 80 µg/L or when the resistance mutation H274Y developed.

    National Category
    Pathobiology
    Identifiers
    urn:nbn:se:uu:diva-160965 (URN)10.7589/2011-11-335 (DOI)000313538100011 ()
    Available from: 2011-11-03 Created: 2011-11-03 Last updated: 2017-12-08Bibliographically approved
    4. Oseltamivir- and Zanamivir-Resistance Related Mutations in Influenza A Viruses Isolated from Wild Mallards in Sweden Studied by a Colorimetric Neuraminidase Inhibition Assay
    Open this publication in new window or tab >>Oseltamivir- and Zanamivir-Resistance Related Mutations in Influenza A Viruses Isolated from Wild Mallards in Sweden Studied by a Colorimetric Neuraminidase Inhibition Assay
    Show others...
    (English)Manuscript (preprint) (Other academic)
    Abstract [en]

     

    Resistance to neuraminidase inhibitors (NAIs) is a growing problem in the battle against influenza A viruses. However, little is known about the resistance of viruses isolated from dabbling ducks, the natural reservoir of the influenza virus. To date, no low-pathogenic avian influenza (LPAI) virus functionally resistant to NAIs has been detected. The aim of this study was to investigate mallard isolates of influenza A virus previously identified to carry oseltamivir carboxylate (OC)- or zanamivir (ZA)-related resistance mutations. In this work, 21 viruses belonging to the N1, N3, N6 and N9 subtypes were analyzed using a colorimetric NA inhibition assay. The R118K mutation was the most frequently observed; it was seen in all subtypes except for N6. IC50 values confirmed the differences in sensitivity to OC or ZA previously observed in the N1 and N2 groups of NAs. Furthermore, both negative controls (NCs) in the N6 and one NC in the N9 subtype were less sensitive to ZA than were genotypically related mutants of the respective subtypes. The presence of OC- and ZA-related mutations in the NA of viruses isolated from wild birds did not result in a NAI-resistant phenotype in this study. The R118K and R152K mutations seemed to somewhat increase the sensitivity to both NAIs compared to WT viruses which supports the thought that the mutations were a result of natural NA variation and not induced by NAI residuals in the environment. Although not resulting in a NAI resistant phenotype, the finding of the mutations D151N and I222V shows that mutations with the potential to enhance NAI resistance exist in the pool of LPAI viruses which stresses the need for surveillance of NAI resistance in wild birds.

    National Category
    Microbiology in the medical area Microbiology
    Identifiers
    urn:nbn:se:uu:diva-160966 (URN)
    Available from: 2011-11-03 Created: 2011-11-03 Last updated: 2018-01-12
  • 29.
    Järhult, Josef D
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Tamiflu: What we know about its ups and downs2015In: British Journal of Virology, ISSN 2055-6128, Vol. 2, no 3, p. 49-52Article in journal (Refereed)
    Abstract [en]

    The pros and cons of the anti-influenza drug oseltamivir (Tamiflu®) have been intensely debated lately. This article aims to sum up what is known about positive and negative effects of the drug. The available data suggests that oseltamivir treatment of uncomplicated influenza in otherwise healthy patients shortens influenza symptoms with approximately 24 hours, and increases nausea and vomiting by 3-5%. Whether oseltamivir treatment has an effect on the frequency of influenza complications or not remains controversial. Oseltamivir is still standard as prophylaxis, treatment of severely ill patients and patients with risk factors for severe influenza disease as well as an important part of pandemic preparedness plans. Resistance development is a potential problem both in treated humans and in the environment. The use of oseltamivir for treatment of uncomplicated influenza in otherwise healthy patients should be questioned.

  • 30.
    Järhult, Josef D.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Muradrasoli, Shaman
    Wahlgren, John
    Söderström, Hanna
    Orozovic, Goran
    Gunnarsson, Gunnar
    Bröjer, Caroline
    Latorre-Margalef, Neus
    Fick, Jerker
    Grabic, Roman
    Lennerstrand, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Microbiology and Infectious Medicine, Clinical Virology.
    Waldenström, Jonas
    Lundkvist, Åke
    Olsen, Björn
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Environmental Levels of the Antiviral Oseltamivir Induce Development of Resistance Mutation H274Y in Influenza A/H1N1 Virus in Mallards2011In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 6, no 9, p. e24742-Article in journal (Refereed)
    Abstract [en]

    Oseltamivir (Tamiflu (R)) is the most widely used drug against influenza infections and is extensively stockpiled worldwide as part of pandemic preparedness plans. However, resistance is a growing problem and in 2008-2009, seasonal human influenza A/H1N1 virus strains in most parts of the world carried the mutation H274Y in the neuraminidase gene which causes resistance to the drug. The active metabolite of oseltamivir, oseltamivir carboxylate (OC), is poorly degraded in sewage treatment plants and surface water and has been detected in aquatic environments where the natural influenza reservoir, dabbling ducks, can be exposed to the substance. To assess if resistance can develop under these circumstances, we infected mallards with influenza A/H1N1 virus and exposed the birds to 80 ng/L, 1 mu g/L and 80 mu g/L of OC through their sole water source. By sequencing the neuraminidase gene from fecal samples, we found that H274Y occurred at 1 mu g/L of OC and rapidly dominated the viral population at 80 mu g/L. IC(50) for OC was increased from 2-4 nM in wild-type viruses to 400-700 nM in H274Y mutants as measured by a neuraminidase inhibition assay. This is consistent with the decrease in sensitivity to OC that has been noted among human clinical isolates carrying H274Y. Environmental OC levels have been measured to 58-293 ng/L during seasonal outbreaks and are expected to reach mu g/L-levels during pandemics. Thus, resistance could be induced in influenza viruses circulating among wild ducks. As influenza viruses can cross species barriers, oseltamivir resistance could spread to human-adapted strains with pandemic potential disabling oseltamivir, a cornerstone in pandemic preparedness planning. We propose surveillance in wild birds as a measure to understand the resistance situation in nature and to monitor it over time. Strategies to lower environmental levels of OC include improved sewage treatment and, more importantly, a prudent use of antivirals.

  • 31.
    Järhult, Josef D
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Stedt, Johan
    Gustafsson, Lars
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Genetics, Animal ecology.
    Zero prevalence of extended spectrum beta-lactamase-producing bacteria in 300 breeding Collared Flycatchers in Sweden2013In: Infection Ecology & Epidemiology, ISSN 2000-8686, E-ISSN 2000-8686, Vol. 3Article in journal (Refereed)
    Abstract [en]

    Wild birds are important indicators and potential spreaders of antibiotic resistance. The order Passerines is scarcely studied apart from Corvus sp. but extended spectrum beta-lactamases (ESBLs) has been found in Blackbirds. We tested 300 fecal samples from a well-studied population of Collared Flycatchers (Ficedula albicollis) at the Island of Gotland in Sweden and found no ESBL-producing bacteria. These results support the idea of 'ecological guild' as Blackbirds are ground-foraging invertebrate feeders, whereas Collared Flycatchers are aerial insectivores not regularly coming into contact with fecal contaminations and therefore less prone to acquire pathogens spread by the fecal-oral route.

  • 32.
    Järhult, Josef D
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Wahlgren, John
    Hasan, Badrul
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Salaneck, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Lundkvist, Åke
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Mallard or chicken?: Comparing the isolation of avian influenza A viruses in embryonated Mallard and chicken eggs2015In: Infection Ecology & Epidemiology, ISSN 2000-8686, E-ISSN 2000-8686, Vol. 5, article id 28458Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: To date, the most efficient and robust method for isolating avian influenza A viruses (IAVs) is using embryonated chicken eggs (ECEs). It is known that low-pathogenic avian IAVs undergo rapid genetic changes when introduced to poultry holdings, but the factors driving mutagenesis are not well understood. Despite this, there is limited data on the effects of the standard method of virus isolation of avian-derived viruses, that is, whether isolation in ECEs causes adaptive changes in avian IAVs. Eggs from a homologous species could potentially offer an isolation vessel less prone to induce adaptive changes.

    METHODS: We performed eight serial passages of two avian IAVs isolated from fecal samples of wild Mallards in both ECEs and embryonated Mallard eggs, and hemagglutination assay titers and hemagglutinin sequences were compared.

    RESULTS: There was no obvious difference in titers between ECEs and embryonated Mallard eggs. Sequence analyses of the isolates showed no apparent difference in the rate of introduction of amino acid substitutions in the hemagglutinin gene (three substitutions in total in embryonated Mallard eggs and two substitutions in ECEs).

    CONCLUSION: Embryonated Mallard eggs seem to be good isolation vessels for avian IAVs but carry some practical problems such as limited availability and short egg-laying season of Mallards. Our study finds isolation of Mallard-derived avian IAVs in ECEs non-inferior to isolation in embryonated Mallard eggs, but more research in the area may be warranted as this is a small-scale study.

  • 33. Lindberg, Richard H.
    et al.
    Fedorova, Ganna
    Blum, Kristin M.
    Pulit-Prociak, Jolanta
    Gillman, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Microbiology and Infectious Medicine. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Järhult, Josef
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Microbiology and Infectious Medicine. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Appelblad, Patrik
    Soderstrom, Hanna
    Online solid phase extraction liquid chromatography using bonded zwitterionic stationary phases and tandem mass spectrometry for rapid environmental trace analysis of highly polar hydrophilic compounds - Application for the antiviral drug Zanamivir2015In: Talanta: The International Journal of Pure and Applied Analytical Chemistry, ISSN 0039-9140, E-ISSN 1873-3573, Vol. 141, p. 164-169Article in journal (Refereed)
    Abstract [en]

    Zanamivir (Za) is a highly polar and hydrophilic antiviral drug used for the treatment of influenza A viruses. Za has been detected in rivers of Japan and it's environmental occurrence has the risk of inducing antiviral resistant avian influenza viruses. In this study, a rapid automated online solid phase extraction liquid chromatography method using bonded zwitterionic stationary phases and tandem mass spectrometry (SPE/LC-MS/MS) for trace analysis of Za was developed. Furthermore, an internal standard (IS) calibration method capable of quantifying Za in Milli-Q surface water, sewage effluent and sewage influent was evaluated. Optimum pre-extraction sample composition was found to be 95/5 v/v acetonitrile/water sample and 1% formic acid. The developed method showed acceptable linearities (r(2) >= 0.994), filtration recovery (>= 91%), and intra-day precisions (RSD <= 16%), and acceptable and environmentally relevant LOQs ( <= 20 ng L-1). Storage tests showed no significant losses of Za during 20 days and +4/-20 degrees C ( <= 12%) with the exception of influent samples, which should be kept at -20 degrees C to avoid significant Za losses. The applicability of the method was demonstrated in a study on phototransformation of Za in unfiltered and filtered surface water during 28 days of artificial UV irradiation exposure. No significant ( <= 12%) phototransformation was found in surface water after 28 days suggesting a relatively high photostability of Za and that Za should be of environmental concern.

  • 34.
    Ling, Jiaxin
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Verner-Carlsson, Jenny
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Eriksson, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Plyusnina, Angelina
    Univ Helsinki, Dept Virol, Med, Helsinki, Finland.
    Löhmus, Mare
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Karolinska Inst, Inst Environm Med, Stockholm, Sweden;Stockholm Cty Council, Ctr Occupat & Environm Med, Stockholm, Sweden;Natl Vet Inst, Uppsala, Sweden.
    Järhult, Josef D.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    van de Goot, Frank
    Symbiant Pathol Expert Ctr, Alkmaar, Netherlands.
    Plyusnin, Alexander
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Univ Helsinki, Dept Virol, Med, Helsinki, Finland.
    Lundkvist, Åke
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Sironen, Tarja
    Univ Helsinki, Dept Virol, Med, Helsinki, Finland.
    Genetic analyses of Seoul hantavirus genome recovered from rats (Rattus norvegicus) in the Netherlands unveils diverse routes of spread into Europe2019In: Journal of Medical Virology, ISSN 0146-6615, E-ISSN 1096-9071, Vol. 91, no 5, p. 724-730Article in journal (Refereed)
    Abstract [en]

    Seoul virus (SEOV) is the etiologic agent of hemorrhagic fever with renal syndrome. It is carried by brown rats (Rattus norvegicus), a commensal rodent that closely cohabitates with humans in urban environments. SEOV has a worldwide distribution, and in Europe, it has been found in rats in UK, France, Sweden, and Belgium, and human cases of SEOV infection have been reported in Germany, UK, France, and Belgium. In the search of hantaviruses in brown rats from the Netherlands, we found both serological and genetic evidence for the presence of SEOV in the local wild rat population. To further decipher the relationship with other SEOV variants globally, the complete genome of SEOV in the Netherlands was recovered. SEOV sequences obtained from three positive rats (captured at close trapping locations at the same time) were found highly similar. Phylogenetic analyses demonstrated that two lineages of SEOV circulate in Europe. Strains from the Netherlands and UK, together with the Baxter strain from US, constitute one of these two, while the second includes strains from Europe and Asia. Our results support a hypothesis of diverse routes of SEOV spread into Europe. These findings, combined with other indications on the expansion of the spatial European range of SEOV, suggest an increased risk of this virus for the public health, highlighting the need for increased surveillance.

  • 35. Lubick, Naomi
    et al.
    Järhult, Josef D.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Resistance in the wild: Q&A: Keeping antivirals viable2019In: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 573, no 7774, p. S53-S53Article in journal (Other academic)
  • 36.
    Nykvist, Marie
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Gillman, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Söderström Lindström, Hanna
    Umeå University, Department of Public Health and Clinical Medicine, Occupational and Environmental Medicine.
    Tang, Chaojun
    Umeå University, Department of Chemistry.
    Fedorova, Ganna
    University of South Bohemia in Ceske Budejovice, Faculty of Fisheries and Protection of Waters, South Bohemian Research Center of Aquaculture and Biodiversity of Hydrocenoses, Vodnany, Czech Republic.
    Lundkvist, Åke
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Latorre-Margalef, Neus
    Linnaeus University, Faculty of Health and Life Sciences, 6. Centre for Ecology and Evolution in Microbial Model Systems (EEMiS).
    Wille, Michelle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Järhult, Josef D.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    In vivo mallard experiments indicate that zanamivir has less potential for environmental influenza A virus resistance development than oseltamivir2017In: Journal of General Virology, ISSN 0022-1317, E-ISSN 1465-2099, Vol. 98, no 12, p. 2937-2949Article in journal (Refereed)
    Abstract [en]

    Neuraminidase inhibitors are a cornerstone of influenza pandemic preparedness before vaccines can be mass-produced and thus a neuraminidase inhibitor-resistant pandemic is a serious threat to public health. Earlier work has demonstrated the potential for development and persistence of oseltamivir resistance in influenza A viruses exposed to environmentally relevant water concentrations of the drug when infecting mallards, the natural influenza reservoir that serves as the genetic base for human pandemics. As zanamivir is the major second-line neuraminidase inhibitor treatment, this study aimed to assess the potential for development and persistence of zanamivir resistance in an in vivo mallard model; especially important as zanamivir will probably be increasingly used. Our results indicate less potential for development and persistence of resistance due to zanamivir than oseltamivir in an environmental setting. This conclusion is based on: (1) the lower increase in zanamivir IC50 conferred by the mutations caused by zanamivir exposure (2-17-fold); (2) the higher zanamivir water concentration needed to induce resistance (at least 10 µg l-1); (3) the lack of zanamivir resistance persistence without drug pressure; and (4) the multiple resistance-related substitutions seen during zanamivir exposure (V116A, A138V, R152K, T157I and D199G) suggesting lack of one straight-forward evolutionary path to resistance. Our study also adds further evidence regarding the stability of the oseltamivir-induced substitution H275Y without drug pressure, and demonstrates the ability of a H275Y-carrying virus to acquire secondary mutations, further boosting oseltamivir resistance when exposed to zanamivir. Similar studies using influenza A viruses of the N2-phylogenetic group of neuraminidases are recommended.

  • 37. Orozovic, Goran
    et al.
    Järhult, Josef D.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Orozovic, Kanita
    Tolf, Conny
    Latorre-Margalef, Neus
    Lennerstrand, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Microbiology and Infectious Medicine, Clinical Virology.
    Olsen, Björn
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Oseltamivir- and Zanamivir-Resistance Related Mutations in Influenza A Viruses Isolated from Wild Mallards in Sweden Studied by a Colorimetric Neuraminidase Inhibition AssayManuscript (preprint) (Other academic)
    Abstract [en]

     

    Resistance to neuraminidase inhibitors (NAIs) is a growing problem in the battle against influenza A viruses. However, little is known about the resistance of viruses isolated from dabbling ducks, the natural reservoir of the influenza virus. To date, no low-pathogenic avian influenza (LPAI) virus functionally resistant to NAIs has been detected. The aim of this study was to investigate mallard isolates of influenza A virus previously identified to carry oseltamivir carboxylate (OC)- or zanamivir (ZA)-related resistance mutations. In this work, 21 viruses belonging to the N1, N3, N6 and N9 subtypes were analyzed using a colorimetric NA inhibition assay. The R118K mutation was the most frequently observed; it was seen in all subtypes except for N6. IC50 values confirmed the differences in sensitivity to OC or ZA previously observed in the N1 and N2 groups of NAs. Furthermore, both negative controls (NCs) in the N6 and one NC in the N9 subtype were less sensitive to ZA than were genotypically related mutants of the respective subtypes. The presence of OC- and ZA-related mutations in the NA of viruses isolated from wild birds did not result in a NAI-resistant phenotype in this study. The R118K and R152K mutations seemed to somewhat increase the sensitivity to both NAIs compared to WT viruses which supports the thought that the mutations were a result of natural NA variation and not induced by NAI residuals in the environment. Although not resulting in a NAI resistant phenotype, the finding of the mutations D151N and I222V shows that mutations with the potential to enhance NAI resistance exist in the pool of LPAI viruses which stresses the need for surveillance of NAI resistance in wild birds.

  • 38. Orozovic, Goran
    et al.
    Orozovic, Kanita
    Järhult, Josef D
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Olsen, Björn
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Study of oseltamivir and zanamivir resistance-related mutations in influenza viruses isolated from wild mallards in Sweden2014In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 9, no 2, p. e89306-Article in journal (Refereed)
    Abstract [en]

    Resistance to neuraminidase inhibitors (NAIs) is a growing problem in battle against influenza A virus. However, little is known about the resistance of viruses isolated from dabbling ducks, the natural reservoir of the influenza virus. To our knowledge, no low-pathogenic avian influenza (LPAI) virus resistant to NAIs has been detected. The aim of this study was to investigate mallard isolates of influenza A virus previously identified to carry oseltamivir carboxylate (OC) or zanamivir (ZA) resistance-related mutations. In this work, 21 viruses belonging to the N1, N3, N6 and N9 subtypes were analyzed using a colorimetric NA inhibition assay. The results of assay showed no NAIs-resistant phenotype for any of the viruses. The R118K mutation was the most recurrent, as it was observed in all subtypes except for N6. IC50 values confirmed the differences in sensitivity to OC or ZA observed in the N1 and N2 groups of NAs. Furthermore, both wild types (WTs) in the N6 and one WT in the N9 subtype were less sensitive to ZA than were genotypically related mutants with R152K and R118K change in the respective subtypes. This may indicate that these and probably even other NAIs resistance-related mutations found in our virus collection were not induced by NAIs residuals in the environment and that the impact of such mutations in an avian influenza could be dependent on subtype, strain and host species.

  • 39. Ramey, AM
    et al.
    Hernandez, J
    Tyrlöv, V
    Uher-Koch, BD
    Schmutz, JA
    Atterby, Clara
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Järhult, Josef D.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Bonnedahl, J
    Antibiotic-resistant Escherichia coli in migratory birds inhabiting remote Alaska.2018In: EcoHealth, ISSN 1612-9202, E-ISSN 1612-9210, Vol. 15, no 1, p. 72-81Article in journal (Refereed)
    Abstract [en]

    We explored the abundance of antibiotic-resistant Escherichia coli among migratory birds at remote sites in Alaska and used a comparative approach to speculate on plausible explanations for differences in detection among species. At a remote island site, we detected antibiotic-resistant E. coli phenotypes in samples collected from glaucous-winged gulls (Larus glaucescens), a species often associated with foraging at landfills, but not in samples collected from black-legged kittiwakes (Rissa tridactyla), a more pelagic gull that typically inhabits remote areas year-round. We did not find evidence for antibiotic-resistant E. coli among 347 samples collected primarily from waterfowl at a second remote site in western Alaska. Our results provide evidence that glaucous-winged gulls may be more likely to be infected with antibiotic-resistant E. coli at remote breeding sites as compared to sympatric black-legged kittiwakes. This could be a function of the tendency of glaucous-winged gulls to forage at landfills where antibiotic-resistant bacterial infections may be acquired and subsequently dispersed. The low overall detection of antibiotic-resistant E. coli in migratory birds sampled at remote sites in Alaska is consistent with the premise that anthropogenic inputs into the local environment or the relative lack thereof influences the prevalence of antibiotic-resistant bacteria among birds inhabiting the area.

  • 40.
    Sandegren, Linus
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Stedt, Johan
    Centre for Ecology and Evolution in Microbial Model Systems, School of Natural Sciences, Linnaeus University, Kalmar Sweden.
    Lustig, Ulrika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Bonnedahl, Jonas
    Centre for Ecology and Evolution in Microbial Model Systems, School of Natural Sciences, Linnaeus University, Kalmar Sweden.
    Andersson, Dan I
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Microbiology.
    Järhult, Josef D.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Long-term carriage and rapid transmission of extended spectrum beta-lactamase-producing E. coli within a flock of Mallards in the absence of antibiotic selection2018In: Environmental Microbiology Reports, ISSN 1758-2229, E-ISSN 1758-2229, Vol. 10, no 5, p. 576-582Article in journal (Refereed)
    Abstract [en]

    Wild birds have been suggested as transmitters and reservoirs for antibiotic resistant bacteria. We performed an experimental study investigating carriage time and interindividual transmission of extended spectrum beta‐lactamase‐ (ESBL‐)producing Escherichia coli in Mallards (Anas platyrhynchos) to assess if the birds carry the bacteria long enough to transfer them geographically during migration. Mallards were inoculated intraoesophageally with four different strains of ESBL‐producing E. coli and kept together in a flock. The ESBL‐strains belonged to sequence types previously shown to spread between birds and humans. Culturing from faecal samples showed presence of ESBL‐producing E. coli the entire 29 day experimental period. An extensive and rapid transmission of the different ESBL‐strains between individuals (including non‐inoculated controls) was observed. In necropsy samples, we detected ESBL‐strains in the cecum even in faeces‐negative birds, indicating that this part of the intestine could function as a reservoir of resistant bacteria. We demonstrate that birds can carry ESBL‐producing E. coli for long enough times to travel far during migration and the extensive interindividual transmission suggests spread between individuals in a dense bird population as a mechanism that allow persistence of resistant bacteria.

  • 41. Singer, Andrew C
    et al.
    Järhult, Josef D
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Grabic, Roman
    Khan, Ghazanfar A
    Fedorova, Ganna
    Fick, Jerker
    Lindberg, Richard H
    Bowes, Michael J
    Olsen, Björn
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Söderström, Hanna
    Compliance to Oseltamivir among Two Populations in Oxfordshire, United Kingdom Affected by Influenza A(H1N1)pdm09, November 2009 - A Waste Water Epidemiology Study.2013In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 8, no 4, p. e60221-Article in journal (Refereed)
    Abstract [en]

    Antiviral provision remains the focus of many pandemic preparedness plans, however, there is considerable uncertainty regarding antiviral compliance rates. Here we employ a waste water epidemiology approach to estimate oseltamivir (Tamiflu®) compliance. Oseltamivir carboxylate (oseltamivir's active metabolite) was recovered from two waste water treatment plant (WWTP) catchments within the United Kingdom at the peak of the autumnal wave of the 2009 Influenza A (H1N1)pdm09 pandemic. Predictions of oseltamivir consumption from detected levels were compared with two sources of national government statistics to derive compliance rates. Scenario and sensitivity analysis indicated between 3-4 and 120-154 people were using oseltamivir during the study period in the two WWTP catchments and a compliance rate between 45-60%. With approximately half the collected antivirals going unused, there is a clear need to alter public health messages to improve compliance. We argue that a near real-time understanding of drug compliance at the scale of the waste water treatment plant (hundreds to millions of people) can potentially help public health messages become more timely, targeted, and demographically sensitive, while potentially leading to less mis- and un-used antiviral, less wastage and ultimately a more robust and efficacious pandemic preparedness plan.

  • 42. Singer, Andrew C.
    et al.
    Järhult, Josef D
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Grabic, Roman
    Khan, Ghazanfar A.
    Lindberg, Richard H.
    Fedorova, Ganna
    Fick, Jerker
    Bowes, Michael J.
    Olsen, Björn
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Soderstrom, Hanna
    Intra- and Inter-Pandemic Variations of Antiviral, Antibiotics and Decongestants in Wastewater Treatment Plants and Receiving Rivers2014In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 9, no 9, p. e108621-Article in journal (Refereed)
    Abstract [en]

    The concentration of eleven antibiotics (trimethoprim, oxytetracycline, ciprofloxacin, azithromycin, cefotaxime, doxycycline, sulfamethoxazole, erythromycin, clarithromycin, ofloxacin, norfloxacin), three decongestants (naphazoline, oxymetazoline, xylometazoline) and the antiviral drug oseltamivir's active metabolite, oseltamivir carboxylate (OC), were measured weekly at 21 locations within the River Thames catchment in England during the month of November 2009, the autumnal peak of the influenza A[H1N1]pdm09 pandemic. The aim was to quantify the pharmaceutical response to the pandemic and compare this to drug use during the late pandemic (March 2010) and the inter-pandemic periods (May 2011). A large and small wastewater treatment plant (WWTP) were sampled in November 2009 to understand the differential fate of the analytes in the two WWTPs prior to their entry in the receiving river and to estimate drug users using a wastewater epidemiology approach. Mean hourly OC concentrations in the small and large WWTP's influent were 208 and 350 ng/L (max, 2070 and 550 ng/L, respectively). Erythromycin was the most concentrated antibiotic measured in Benson and Oxford WWTPs influent (max = 6,870 and 2,930 ng/L, respectively). Napthazoline and oxymetazoline were the most frequently detected and concentrated decongestant in the Benson WWTP influent (1650 and 67 ng/L) and effluent (696 and 307 ng/L), respectively, but were below detection in the Oxford WWTP. OC was found in 73% of November 2009's weekly river samples (max = 193 ng/L), but only in 5% and 0% of the late-and inter-pandemic river samples, respectively. The mean river concentration of each antibiotic during the pandemic largely fell between 17-74 ng/L, with clarithromycin (max = 292 ng/L) and erythromycin (max = 448 ng/L) yielding the highest single measure. In general, the concentration and frequency of detecting antibiotics in the river increased during the pandemic. OC was uniquely well-suited for the wastewater epidemiology approach owing to its nature as a prodrug, recalcitrance and temporally-and spatially-resolved prescription statistics.

  • 43.
    Strand, Tanja M.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Department of Microbiology, National Veterinary Institute (SVA), Uppsala, Sweden.
    Pineda, Sebastian
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Backhans, Annette
    Jakobsen, Frida
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Råsbäck, Therese
    Lõhmus, Mare
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Institute for Environmental Medicine, Karolinska Institute, Stockholm, Sweden;Centre for Occupational and Environmental Medicine, Stockholm County Council, Stockholm, Sweden.
    Järhult, Josef D.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infection medicine.
    Lundkvist, Åke
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Detection of Leptospira in Urban Swedish Rats: Pest Control Interventions as a Promising Source of Rats Used for Surveillance2019In: Vector Borne and Zoonotic Diseases, ISSN 1530-3667, E-ISSN 1557-7759, Vol. 19, no 6, p. 414-420Article in journal (Refereed)
    Abstract [en]

    Rat carcasses obtained from pest control interventions can potentially be used for an efficient surveillance of zoonotic diseases such as leptospirosis. To evaluate the performance of different laboratory methods for detection of pathogenic Leptospira spp., heart and kidney samples from wild Norway rats were analyzed by microscopic agglutination test (MAT, the gold standard), a commercial IgG enzyme-linked immunosorbent assay, and by an optimized quantitative PCR (secY qPCR, followed by sequencing). We found secY qPCR to be as sensitive as MAT for screening of Leptospira infection in pest control rats and selected secY qPCR for a larger screening of rats from urban and rural areas in central and southern Sweden. We identified secY qPCR positive rats from the cities Stockholm, Gothenburg, and Malmö, which were further confirmed by sequencing.

  • 44. Svebrant, Sofia
    et al.
    Olsen, Therese
    Larsson, Jim
    Öhagen, Patrik
    Söderström, Hanna
    Järhult, Josef D.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    The enzyme toilet rim block “pCure” does not efficiently remove drug residues in a hospital setting - exemplifying the importance of on-site implementation testing2018In: Infection Ecology & Epidemiology, ISSN 2000-8686, E-ISSN 2000-8686, Vol. 8, no 1Article in journal (Refereed)
  • 45.
    Wille, Michelle
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Peter Doherty Inst Infect & Immun, WHO Collaborating Ctr Reference & Res Influenza, Melbourne, Vic, Australia.
    Bröjer, Caroline
    Lundkvist, Åke
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Järhult, Josef D.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Alternate routes of influenza A virus infection in Mallard (Anas platyrhynchos)2018In: Veterinary research (Print), ISSN 0928-4249, E-ISSN 1297-9716, Vol. 49, article id 110Article in journal (Refereed)
  • 46.
    Wille, Michelle
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Lindqvist, Kristine
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Muradrasoli, Shaman
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Department of Laboratory Medicine, Division of Clinical Microbiology, Karolinska Institute, Karolinska University Hospital, SE-14186 Huddinge, Sweden.
    Olsen, Björn
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Järhult, Josef D.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Urbanization and the dynamics of RNA viruses in Mallards (Anas platyrhynchos)2017In: Infection, Genetics and Evolution, ISSN 1567-1348, E-ISSN 1567-7257, Vol. 51, p. 89-97Article in journal (Refereed)
    Abstract [en]

    Urbanization is intensifying worldwide, and affects the epidemiology of infectious diseases. However, the effect of urbanization on natural host-pathogen systems remains poorly understood. Urban ducks occupy an interesting niche in that they directly interact with both humans and wild migratory birds, and either directly or indirectly with food production birds. Here we have collected samples from Mallards (Anas platyrhynchos) residing in a pond in central Uppsala, Sweden, from January 2013 to January 2014. This artificial pond is kept ice-free during the winter months, and is a popular location where the ducks are fed, resulting in a resident population of ducks year-round. Nine hundred and seventy seven (977) fecal samples were screened for RNA viruses including: influenza A virus (IAV), avian paramyxovirus 1, avian coronavirus (CoV), and avian astrovirus (AstroV). This intra-annual dataset illustrates that these RNA viruses exhibit similar annual patterns to IAV, suggesting similar ecological factors are at play. Furthermore, in comparison to wild ducks, autumnal prevalence of IAV and CoV are lower in this urban population. We also demonstrate that AstroV might be a larger burden to urban ducks than IAV, and should be better assessed to demonstrate the degree to which wild birds contribute to the epidemiology of these viruses. The presence of economically relevant viruses in urban Mallards highlights the importance of elucidating the ecology of wildlife pathogens in urban environments, which will become increasingly important for managing disease risks to wildlife, food production animals, and humans.

  • 47.
    Wille, Michelle
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Muradrasoli, Shaman
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Swedish Univ Agr Sci, Dept Biomed Sci & Vet Publ Hlth, Uppsala, Sweden.
    Nilsson, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Microbiology and Infectious Medicine.
    Järhult, Josef D
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    High Prevalence and Putative Lineage Maintenance of Avian Coronaviruses in Scandinavian Waterfowl.2016In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 11, no 3, article id e0150198Article in journal (Refereed)
    Abstract [en]

    Coronaviruses (CoVs) are found in a wide variety of wild and domestic animals, and constitute a risk for zoonotic and emerging infectious disease. In poultry, the genetic diversity, evolution, distribution and taxonomy of some coronaviruses have been well described, but little is known about the features of CoVs in wild birds. In this study we screened 764 samples from 22 avian species of the orders Anseriformes and Charadriiformes in Sweden collected in 2006/2007 for CoV, with an overall CoV prevalence of 18.7%, which is higher than many other wild bird surveys. The highest prevalence was found in the diving ducks-mainly Greater Scaup (Aythya marila; 51.5%)-and the dabbling duck Mallard (Anas platyrhynchos; 19.2%). Sequences from two of the Greater Scaup CoV fell into an infrequently detected lineage, shared only with a Tufted Duck (Aythya fuligula) CoV. Coronavirus sequences from Mallards in this study were highly similar to CoV sequences from the sample species and location in 2011, suggesting long-term maintenance in this population. A single Black-headed Gull represented the only positive sample from the order Charadriiformes. Globally, Anas species represent the largest fraction of avian CoV sequences, and there seems to be no host species, geographical or temporal structure. To better understand the eitiology, epidemiology and ecology of these viruses more systematic surveillance of wild birds and subsequent sequencing of detected CoV is imperative.

  • 48.
    Wille, Michelle
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Yin, Hong
    Department of Laboratory Medicine, Division of Clinical Microbiology, Dalarna County, Sweden.
    Lundkvist, Åke
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Xu, Juan
    Capital Med Univ, Xuanwu Hosp, Beijing, Peoples R China..
    Muradrasoli, Shaman
    Karolinska Inst, Karolinska Univ Hosp, Div Clin Microbiol, Dept Lab Med, SE-14186 Huddinge, Sweden..
    Järhult, Josef D.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases. Uppsala Univ, Infect Dis Sect, Dept Med Sci, Uppsala, Sweden..
    RNAlater (R) is a viable storage option for avian influenza sampling in logistically challenging conditions2018In: Journal of Virological Methods, ISSN 0166-0934, E-ISSN 1879-0984, Vol. 252, p. 32-36Article in journal (Refereed)
    Abstract [en]

    Surveillance of wild birds is critical in monitoring for highly pathogenic avian influenza A viruses (ATVs). However, a successful surveillance regime requires proper treatment of samples in the field - rapid placement of samples in -80 degrees C and subsequent maintenance of cold-chain. Given the logistical difficulties of this, many avian taxa and/or geographic locations are not sampled, or, when sampled may result in false negatives due to poor sample treatment in the field. Here, we assessed the utility of RNAlater (R) as a stabilization agent for AIV sampling. We found no difference in real time PCR performance between virus transport media at optimal conditions and RNAlater (R) at -80 degrees C, -20 degrees C, 4 degrees C or room temperature up to two weeks, at either low or high virus load. Not only was RNAlater (R) useful in comparison of spiked samples or those from duck experiments, it was employed successfully in a field study of backyard birds in China. We detected AIV in cloacal and oropharyngeal samples from chickens and a sample with a low Cq was successfully subtyped as H9, although sample storage conditions were suboptimal. Thus, despite limitations in downstream characterization such virus isolation and typing, RNAlater (R) is a viable option for AIV sampling under logistically challenging circumstances.

  • 49.
    Zink, Eren
    et al.
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Arts, Department of Cultural Anthropology and Ethnology.
    Elvander, Marianne
    Lindberg, Ann
    Järhult, Josef D.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Målqvist, Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, International Maternal and Child Health (IMCH), International Child Health and Nutrition.
    Boqvist, Sofia
    Bertilsson, Stefan
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Genetics, Limnology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Magnusson, Ulf
    Chandler, Rebecca
    Hur ska vi klara de nya epidemierna?2017Other (Other (popular science, discussion, etc.))
1 - 49 of 49
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