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Sylvester, B., Gasarasi, D. B., Aboud, S., Tarimo, D., Masawe, S., Mpembeni, R. & Swedberg, G. (2018). Interferon-gamma and Interleukin-10 Responses during Clinical Malaria Episodes in Infants Aged 0-2 Years Prenatally Exposed to Plasmodium falciparum: Tanzanian Birth Cohort. Journal of Tropical Medicine, Article ID 6847498.
Open this publication in new window or tab >>Interferon-gamma and Interleukin-10 Responses during Clinical Malaria Episodes in Infants Aged 0-2 Years Prenatally Exposed to Plasmodium falciparum: Tanzanian Birth Cohort
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2018 (English)In: Journal of Tropical Medicine, ISSN 1687-9686, E-ISSN 1687-9694, article id 6847498Article in journal (Refereed) Published
Abstract [en]

Background: Infants born to mothers with placental malaria are prenatally exposed to Plasmodium falciparum antigens. However, the effect of that exposure to subsequent immune responses has not been fully elucidated. This study aimed at determining the effect of prenatal exposure to P. falciparum on Interleukin-10 and Interferon-gamma responses during clinical malaria episodes in the first 24 months of life.

Methods: This prospective cohort study involved 215 infants aged 0-2 years born to mothers with or without placental malaria. Enzyme-linked immunosorbent assay (ELISA) was used to determine levels of IL-10 and IFN-gamma in infants and detect IgM in cord blood. Data were analyzed using SPSS version 20.

Findings: Geometric mean for IFN-gamma in exposed infants was 557.9 pg/ml (95% CI: 511.6-604.1) and in unexposed infants it was 634.4 pg/ml (95% CI: 618.2-668.5) (P=0.02). Mean IL-10 was 22.4 pg/ml (95% CI: 19.4-28.4) and 15.1 pg/ml (95% CI: 12.4-17.6), respectively (P=0.01).

Conclusions: Prenatal exposure to P. falciparum antigens significantly affects IL-10 and IFN-gamma responses during clinical malaria episodes in the first two years of life.

Place, publisher, year, edition, pages
HINDAWI LTD, 2018
National Category
Immunology
Identifiers
urn:nbn:se:uu:diva-362855 (URN)10.1155/2018/6847498 (DOI)000441634500001 ()30154871 (PubMedID)
Funder
Sida - Swedish International Development Cooperation Agency
Available from: 2018-10-15 Created: 2018-10-15 Last updated: 2018-10-15Bibliographically approved
Lwanira, C. N., Kironde, F., Kaddumukasa, M. & Swedberg, G. (2017). Prevalence of polymorphisms in glucose-6-phosphate dehydrogenase, sickle haemoglobin and nitric oxide synthase genes and their relationship with incidence of uncomplicated malaria in Iganga, Uganda. Malaria Journal, 16, Article ID 322.
Open this publication in new window or tab >>Prevalence of polymorphisms in glucose-6-phosphate dehydrogenase, sickle haemoglobin and nitric oxide synthase genes and their relationship with incidence of uncomplicated malaria in Iganga, Uganda
2017 (English)In: Malaria Journal, ISSN 1475-2875, E-ISSN 1475-2875, Vol. 16, article id 322Article in journal (Refereed) Published
Abstract [en]

Background: Host genetics play an important role in Plasmodium falciparum malaria susceptibility. However, information on host genetic factors and their relationships with malaria in the vaccine trial site of Iganga, Uganda is limited. The main objective of this study was to determine the prevalence of selected host genetic markers and their relationship to malaria incidence in the vaccine trial site of Iganga, Uganda. In a 1-year longitudinal cohort study, 423 children aged below 9 years were recruited and their malaria episodes were investigated. Host genetic polymorphisms were assessed by PCR-RFLP, haemoglobin electrophoresis and DNA sequencing. Using a multivariate negative binomial regression model, estimates of the impact of human genetic polymorphisms on malaria incidence were performed. In all statistical tests, a P value of < 0.05 was considered as significant. Results: The prevalences of sickle cell haemoglobin trait, G6PD c. 202 G > A (rs 1050828) and NOS2 -954 G > C (rs 1800482) variants were 26.6, 22.7 and 17.3%, respectively. Inducible nitric oxide synthase 2 (NOS2 -954 G>C; rs 1800482) heterozygosity was associated with lower incidence of malaria in all age groups {Adjusted incident rates ratio (aIRR) 0.59; 95% CI [0.386-0.887]; P = 0.012)}. About 4% of study subjects had co-existence of sickle cell Hb trait and G6PD deficiency. Sickle cell Hb heterozygotes (Hb AS) aged less than 1 year experienced significantly more malaria episodes annually than children with normal haemoglobin (Hb AA) {aIRR = 1.98; 95% CI [1.240-3.175]; P = 0.004}. There was no significant influence of the sickle cell trait on malaria incidence among older children of 1-9 years. Conclusions: Mutation (NOS2 -954 G > C; rs 1800482) of nitric oxide synthase 2 gene promoter was associated with a lower incidence of acute malaria. The normal haemoglobin (wild genotype; HbAA) was associated with reduced malaria incidence rates during the first year of life. More understanding of the interplay between host genetics and malaria susceptibility is required.

Keywords
Human gene polymorphisms, Plasmodium falciparum malaria, Incidence
National Category
Infectious Medicine Microbiology in the medical area
Identifiers
urn:nbn:se:uu:diva-332663 (URN)10.1186/s12936-017-1970-1 (DOI)000407839500001 ()
Funder
EU, FP7, Seventh Framework Programme, 242095
Available from: 2017-10-31 Created: 2017-10-31 Last updated: 2018-01-13Bibliographically approved
Sylvester, B., Gasarasi, D. B., Aboud, S., Tarimo, D., Massawe, S., Mpembeni, R. & Swedberg, G. (2016). Prenatal exposure to Plasmodium falciparum increases frequency and shortens time from birth to first clinical malaria episodes during the first two years of life: prospective birth cohort study. Malaria Journal, 15, Article ID 379.
Open this publication in new window or tab >>Prenatal exposure to Plasmodium falciparum increases frequency and shortens time from birth to first clinical malaria episodes during the first two years of life: prospective birth cohort study
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2016 (English)In: Malaria Journal, ISSN 1475-2875, E-ISSN 1475-2875, Vol. 15, article id 379Article in journal (Refereed) Published
Abstract [en]

Background: Prenatal exposure to Plasmodium falciparum affects development of protective immunity and susceptibility to subsequent natural challenges with similar parasite antigens. However, the nature of these effects has not been fully elucidated. The aim of this study was to determine the effect of prenatal exposure to P. falciparum on susceptibility to natural malaria infection, with a focus on median time from birth to first clinical malaria episode and frequency of clinical malaria episodes in the first 2 years of life.

Methods: A prospective birth cohort study was conducted in Rufiji district in Tanzania, between January 2013 and December 2015. Infants born to mothers with P. falciparum in the placenta at time of delivery were defined as exposed, and infants born to mothers without P. falciparum parasites in placenta were defined as unexposed. Placental infection was established by histological techniques. Out of 206 infants recruited, 41 were in utero exposed to P. falciparum and 165 infants were unexposed. All infants were monitored for onset of clinical malaria episodes in the first 2 years of life. The outcome measure was time from birth to first clinical malaria episode, defined by fever (>= 37 degrees C) and microscopically determined parasitaemia. Median time to first clinical malaria episode between exposed and unexposed infants was assessed using Kaplan-Meier survival analysis and comparison was done by log rank. Association of clinical malaria episodes with prenatal exposure to P. falciparum was assessed by multivariate binary logistic regression. Comparative analysis of mean number of clinical malaria episodes between exposed and unexposed infants was done using independent sample t test.

Results: The effect of prenatal exposure to P. falciparum infection on clinical malaria episodes was statistically significant (Odds Ratio of 4.79, 95 % CI 2.21-10.38, p < 0.01) when compared to other confounding factors. Median time from birth to first clinical malaria episode for exposed and unexposed infants was 32 weeks (95 % CI 30.88-33.12) and 37 weeks (95 % CI 35.25-38.75), respectively, and the difference was statistically significant (p = 0.003). The mean number of clinical malaria episodes in exposed and unexposed infants was 0.51 and 0.30 episodes/infant, respectively, and the difference was statistically significant (p = 0.038).

Conclusions: Prenatal exposure to P. falciparum shortens time from birth to first clinical malaria episode and increases frequency of clinical malaria episodes in the first 2 years of life.

Keywords
Prenatal exposure, Plasmodium falciparum, Clinical malaria episode, Newborns, Susceptibility
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-301016 (URN)10.1186/s12936-016-1417-0 (DOI)000380101800004 ()27448394 (PubMedID)
Funder
Sida - Swedish International Development Cooperation Agency
Available from: 2016-08-17 Created: 2016-08-17 Last updated: 2017-11-28Bibliographically approved
Lwanira, C. N., Mukasa, M. K., Swedberg, G. & Kironde, F. (2015). Frequency of RANTES gene polymorphisms and their association with incidence of malaria: a longitudinal study on children in Iganga district, Uganda. Malaria Journal, 14, Article ID 341.
Open this publication in new window or tab >>Frequency of RANTES gene polymorphisms and their association with incidence of malaria: a longitudinal study on children in Iganga district, Uganda
2015 (English)In: Malaria Journal, ISSN 1475-2875, E-ISSN 1475-2875, Vol. 14, article id 341Article in journal (Refereed) Published
Abstract [en]

Background: The severity and outcome of malaria is influenced by host immunity in which chemokines such as Regulated upon Activation, Normal T cell Expressed and Secreted (RANTES) play an important role. Previous studies show that variations in the RANTES gene affect RANTES protein production, hence altering host immunity. In this study, the relationship between presence of mutations in RANTES and incidence of malaria in a cohort of children living in a malaria-endemic area of Uganda was determined. Methods: This was a longitudinal study comprising of 423 children aged between 6 months and 9 years, who were actively followed up for 1 year. Malaria episodes occurring in the cohort children were detected and the affected children treated with national policy drug regimen. Mutations in the RANTES gene were determined by PCR-RFLP method and their frequencies were calculated. A multivariate negative binomial regression model was used to estimate the impact of RANTES mutations on malaria incidence. In all statistical tests, a P-value of <0.05 was considered as significant. Results: The frequencies of the -403A and In1.1C allele were 53.7 and 19.2 %, respectively. No mutations were found at the -28 locus. After adjustment of incidence rates for age, blood group, insecticide-treated bed net (ITN) use, malaria history and the sickle cell trait, 1n1.1T/C heterozygotes and homozygotes showed a non-significant trend towards higher incidence rates compared to wild-type individuals (IRR = 1.10; P = 0.55 and IRR = 1.25; P = 0.60, respectively). Similarly, there was no significant difference in malaria incidence rates between RANTES -403G/A heterozygotes or homozygotes and those without mutations (IRR = 1.09; P = 0.66 and IRR = 1.16; P = 0.50, respectively). No relation was seen between RANTES polymorphisms, baseline parasite densities and the time to first re-infection after administration of anti-malaria drugs. Conclusions: This study showed that the -403A mutation occurs in nearly half of the study population and the In1.1C allele occurs in one in every four children. Despite the high frequency of these mutations, there was no clear association with malaria incidence. Other studies evaluating more markers, that could potentially modulate RANTES gene transcription alongside other genetic modifiers of malaria susceptibility, may provide further explanations to these less dramatic findings.

Keywords
RANTES gene polymorphisms, Plasmodium falciparum malaria, Incidence
National Category
Microbiology in the medical area
Identifiers
urn:nbn:se:uu:diva-263431 (URN)10.1186/s12936-015-0875-0 (DOI)000360605100002 ()26341782 (PubMedID)
Funder
EU, FP7, Seventh Framework Programme, 242095 (EVIMALAR)Sida - Swedish International Development Cooperation Agency
Available from: 2015-10-07 Created: 2015-09-30 Last updated: 2018-01-11Bibliographically approved
Golassa, L., Kamugisha, E., Ishengoma, D. S., Baraka, V., Shayo, A., Baliraine, F. N., . . . Swedberg, G. (2015). Identification of large variation in pfcrt, pfmdr-1 and pfubp-1 markers in Plasmodium falciparum isolates from Ethiopia and Tanzania. Malaria Journal, 14, Article ID 264.
Open this publication in new window or tab >>Identification of large variation in pfcrt, pfmdr-1 and pfubp-1 markers in Plasmodium falciparum isolates from Ethiopia and Tanzania
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2015 (English)In: Malaria Journal, ISSN 1475-2875, E-ISSN 1475-2875, Vol. 14, article id 264Article in journal (Refereed) Published
Abstract [en]

Background: Plasmodium falciparum resistance to anti-malarials is a major drawback in effective malaria control and elimination globally. Artemisinin-combination therapy (ACT) is currently the key first-line treatment for uncomplicated falciparum malaria. Plasmodium falciparum genetic signatures at pfmdr-1, pfcrt, and pfubp-1 loci are known to modulate in vivo and in vitro parasite response to ACT. The objective of this study was to assess the distribution of these resistance gene markers in isolates collected from different malaria transmission intensity in Ethiopia and Tanzania. Methods: Plasmodium falciparum clinical isolates were collected from different regions of Ethiopia and Tanzania. Genetic polymorphisms in the genes pfcrt, pfmdr-1 and pfubp-1 were analysed by PCR and sequencing. Frequencies of the different alleles in the three genes were compared within and between regions, and between the two countries. Results: The majority of the isolates from Ethiopia were mutant for the pfcrt 76 and wild-type for pfmdr-1 86. In contrast, the majority of the Tanzanian samples were wild-type for both pfcrt and pfmdr-1 loci. Analysis of a variable linker region in pfmdr-1 showed substantial variation in isolates from Tanzania as compared to Ethiopian isolates that had minimal variation. Direct sequencing of the pfubp-1 region showed that 92.8% (26/28) of the Ethiopian isolates had identical genome sequence with the wild type reference P. falciparum strain 3D7. Of 42 isolates from Tanzania, only 13 (30.9%) had identical genome sequences with 3D7. In the Tanzanian samples, 10 variant haplotypes were identified. Conclusion: The majority of Ethiopian isolates carried the main marker for chloroquine (CQ) resistance, while the majority of the samples from Tanzania carried markers for CQ susceptibility. Polymorphic genes showed substantially more variation in Tanzanian isolates. The low variability in the polymorphic region of pfmdr-1 in Ethiopia may be a consequence of low transmission intensity as compared to high transmission intensity and large variations in Tanzania.

Keywords
Malaria, Plasmodium falciparum, pfcrt, pfmdr-1, pfubp-1, Ethiopia, Tanzania
National Category
Infectious Medicine
Identifiers
urn:nbn:se:uu:diva-259651 (URN)10.1186/s12936-015-0783-3 (DOI)000357564500002 ()26152336 (PubMedID)
Note

Medical Research Council UK  G0600718, Swedish Research Link Grant

Available from: 2015-08-20 Created: 2015-08-10 Last updated: 2017-12-04Bibliographically approved
Golassa, L., Baliraine, F. N., Enweji, N., Erko, B., Swedberg, G. & Aseffa, A. (2015). Microscopic and molecular evidence of the presence of asymptomatic Plasmodium falciparum and Plasmodium vivax infections in an area with low, seasonal and unstable malaria transmission in Ethiopia. BMC Infectious Diseases, 15, Article ID 310.
Open this publication in new window or tab >>Microscopic and molecular evidence of the presence of asymptomatic Plasmodium falciparum and Plasmodium vivax infections in an area with low, seasonal and unstable malaria transmission in Ethiopia
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2015 (English)In: BMC Infectious Diseases, ISSN 1471-2334, E-ISSN 1471-2334, Vol. 15, article id 310Article in journal (Refereed) Published
Abstract [en]

Background: The presence of asymptomatic infections has serious implications for malaria elimination campaigns. Since asymptomatic carriers do not seek treatment for their infection and may become gametocyte carriers, they undoubtedly contribute to the persistence of malaria transmission in a population. The presence of asymptomatic parasitemias was noted in areas with seasonal malaria transmission. In Ethiopia there is a paucity of data regarding the prevalence of asymptomatic malaria carriage. This study was undertaken to assess the presence and prevalence of asymptomatic Plasmodium falciparum and Plasmodium vivax infections in south-central Oromia, Ethiopia. Methods: A total of 1094 apparently healthy individuals >= 2 years of age in south-central Oromia, Ethiopia, an area with seasonal and unstable malaria transmission, were screened for the presence of asymptomatic plasmodial infections. Finger-prick blood samples were taken from each participant for blood film preparation for microscopy and the rapid diagnostic test (RDT). Blood samples were also spotted on Whatman 3MM filter paper for parasite DNA extraction. Results: The prevalence of asymptomatic Plasmodium carriage (P. falciparum, P. vivax and mixed species) was 5.0 % (55/1,094) as determined by microscopy, while the prevalence as determined using RDT was 8.2 % (90/1,094). PCR was done on 47 of 55 microscopy-confirmed and on 79 of 90 RDT-confirmed samples. PCR detected parasite DNA in 89.4 % (42/47) of the microscopy-positive samples and in 77.2 % (61/79) of the RDT-positive samples. No significant difference was observed in the prevalence of asymptomatic P. falciparum or P. vivax infections in the study area (P > 0.1). However, the prevalence of asymptomatic parasitaemia was significantly associated with gender (OR = 0.47, P = 0.015; being higher in males than females) and age (X-2 = 25, P < 0.001; being higher in younger than in older individuals). Age and parasite densities had an inverse relationship. Conclusions: This study confirms the presence of asymptomatic P. falciparum and P. vivax infections in south-central Oromia, an area with low, seasonal and unstable malaria transmission in Ethiopia. Of 55 microscopically confirmed asymptomatic infections, P. falciparum monoinfection accounted for 45.5 % and of 90 RDT positive asymptomatic infections, 66.7 % were P. falciparum. Although not statistically significant, P. falciparum accounted for a relatively large number of the asymptomatic infections as determined by both tests. The prevalence of asymptomatic parasitaemia was highest in the younger age group. HRP-2-based RDTs specific for P. falciparum showed high false positivity rate compared to Plasmodium lactate dehydrogenase (pLDH) specific to P. vivax. Although microscopy and RDT detected substantial numbers of asymptomatic infections in apparently healthy inhabitants, the use of a highly sensitive molecular diagnostics offers a more accurate assessment of the magnitude of asymptomatic infections.

Keywords
Asymptomatic parasitaemia, Microscopy, PCR, Rapid diagnostic tests, Unstable transmission, Plasmodium falciparum, Plasmodium vivax, Ethiopia
National Category
Infectious Medicine
Identifiers
urn:nbn:se:uu:diva-261239 (URN)10.1186/s12879-015-1070-1 (DOI)000358906700004 ()26242405 (PubMedID)
Available from: 2015-09-07 Created: 2015-08-31 Last updated: 2017-12-04Bibliographically approved
Golassa, L., Erko, B., Baliraine, F. N., Aseffa, A. & Swedberg, G. (2015). Polymorphisms in chloroquine resistance-associated genes in Plasmodium vivax in Ethiopia. Malaria Journal, 14, Article ID 164.
Open this publication in new window or tab >>Polymorphisms in chloroquine resistance-associated genes in Plasmodium vivax in Ethiopia
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2015 (English)In: Malaria Journal, ISSN 1475-2875, E-ISSN 1475-2875, Vol. 14, article id 164Article in journal (Refereed) Published
Abstract [en]

Background: Evidence for decreasing chloroquine (CQ) efficacy against Plasmodium vivax has been reported from many endemic countries in the world. In Ethiopia, P. vivax accounts for 40% of all malaria cases and CQ is the first-line drug for vivax malaria. Mutations in multidrug resistance 1 (pvmdr-1) and K10 insertion in the pvcrt-o genes have been identified as possible molecular markers of CQ-resistance (CQR) in P. vivax. Despite reports of CQ treatment failures, no data are currently available on the prevalence of molecular markers of P. vivax resistance in Ethiopia. The objective of this study was to determine the prevalence of mutations in the pvmdr-1 and K10 insertion in the pvcrt-o genes. Methods: A total of 36 P. vivax clinical isolates were collected from West Arsi district in Ethiopia. Sequencing was used to analyse polymorphisms of the pvcrt-o and pvmdr-1 genes. Results: Sequencing results of the pvmdr-1 fragment showed the presence of two non-synonymous mutations at positions 976 and 1076. The Y -> F change at codon 976 (TAC -> TTC) was observed in 21 (75%) of 28 the isolates while the F -> L change (at codon 1076), which was due to a single mutation (TTT -> CTT), was observed in 100% of the isolates. Of 33 samples successfully amplified for the pvcrt-o, the majority of the isolates (93.9%) were wild type, without K10 insertion. Conclusions: High prevalence of mutations in candidate genes conferring CQR in P. vivax was identified. The fact that CQ is still the first-line treatment for vivax malaria, the significance of mutations in the pvcrt-o and pvmdr-1 genes and the clinical response of the patients' to CQ treatment and whether thus an association exists between point mutations of the candidate genes and CQR requires further research in Ethiopia.

Keywords
Chloroquine resistance, Mutations, Plasmodium vivax, Pvcrt-o, Pvmdr-1
National Category
Infectious Medicine
Identifiers
urn:nbn:se:uu:diva-253057 (URN)10.1186/s12936-015-0625-3 (DOI)000353325400001 ()25889237 (PubMedID)
Note

Correction in: Malaria Journal, 2018, 17:188.

https://doi.org/10.1186/s12936-018-2338-x

Available from: 2015-06-12 Created: 2015-05-20 Last updated: 2018-08-28Bibliographically approved
Marwa, K. J., Schmidt, T., Sjögren, M., Minzi, O. M. S., Kamugisha, E. & Swedberg, G. (2014). Cytochrome P450 single nucleotide polymorphisms in an indigenous Tanzanian population: a concern about the metabolism of artemisinin-based combinations. Malaria Journal, 13, 420
Open this publication in new window or tab >>Cytochrome P450 single nucleotide polymorphisms in an indigenous Tanzanian population: a concern about the metabolism of artemisinin-based combinations
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2014 (English)In: Malaria Journal, ISSN 1475-2875, E-ISSN 1475-2875, Vol. 13, p. 420-Article in journal (Refereed) Published
Abstract [en]

Background: Artemisinin-based combinations currently recommended for treatment of uncomplicated Plasmodium falciparum malaria in many countries of sub-Saharan Africa are substrates of CYP enzymes. The cytochrome enzyme system is responsible for metabolism of about 80-90% of clinically used drugs. It is, therefore, important to obtain the pharmacogenetics of the population in the region with respect to these combinations and thereby enable practitioners to predict treatment outcomes. The aim of this study was to detect and determine allelic frequencies of CYP2C8*2, CYP2C8*3, CYP3A4*1B, CYP3A5*3 and CYP2B6*6 variant alleles in a Tanzanian indigenous population. Methods: Genomic DNA extraction from blood obtained from 256 participants who escorted patients at Karume Health Centre in Mwanza Tanzania, was carried out using the Gene JET (TM) Genomic DNA purification kit (Thermo Scientific). Genotyping for the cytochrome P450 variant alleles was performed using predesigned primers. Amplification was done by PCR while differentiation between alleles was done by restriction fragment length polymorphism (PCR-RFLP) (for CYP2C8*2, CYP2C8*3) and sequencing (for CYP2B6*6, CYP3A5*3 and CYP3A4*1B). Results: CYP2C8*2, CYP2C8*3, CYP3A5*3, CYP3A4*1B and CYP2B6*6 variant allelic frequencies were found to be 19,10,16,78 and 36% respectively. Conclusion: Prevalence of CYP2C8*2, CYP3A5*3, CYP3A4*1B and CYP2B6*6 mutations in a Tanzanian population/ subjects are common. The impact of these point mutations on the metabolism of anti-malarial drugs, particularly artemisinin-based combinations, and their potential drug-drug interactions (DDIs) needs to be further evaluated.

Keywords
Cytochrome P450, Artemisinin-based combination therapy, Poor metabolizers, Tanzania, Plasmodium falciparum malaria
National Category
Microbiology in the medical area Infectious Medicine
Identifiers
urn:nbn:se:uu:diva-240230 (URN)10.1186/1475-2875-13-420 (DOI)000346090600001 ()25363545 (PubMedID)
Available from: 2015-01-07 Created: 2015-01-06 Last updated: 2018-01-11Bibliographically approved
Golassa, L., Enweji, N., Erko, B., Aseffa, A. & Swedberg, G. (2014). High prevalence of pfcrt-CVIET haplotype in isolates from asymptomatic and symptomatic patients in south-central Oromia, Ethiopia. Malaria Journal, 13, 120
Open this publication in new window or tab >>High prevalence of pfcrt-CVIET haplotype in isolates from asymptomatic and symptomatic patients in south-central Oromia, Ethiopia
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2014 (English)In: Malaria Journal, ISSN 1475-2875, E-ISSN 1475-2875, Vol. 13, p. 120-Article in journal (Refereed) Published
Abstract [en]

Background: As a result of extensive chloroquine resistance (CQR) in Plasmodium falciparum in late 1990s, Ethiopia replaced CQ with sulphadoxine-pyrimethamine (SP) as first-line drug, which in turn was replaced by artemisinin combination therapy in 2004. Plasmodium falciparum resistance to CQ is determined by the mutation at K76T of the P. falciparum chloroquine resistance transporter (pfcrt) gene. Understanding diversity in the P. falciparum genome is crucial since it has the potential to influence important phenotypes of the parasite such as drug resistance. Limited data is available regarding the type of pfcrt mutant allelic type, the effect of CQ withdrawal and diversity of the parasite population in south-central Oromia, Ethiopia. Methods: Finger-pricked blood spotted on Whatman 3MM filter papers were collected from falciparum malaria patients. Parasite DNA was extracted from individual blood spots on the filter papers. The presence of K76T mutations was determined using nested PCR for all isolates. Complete sequencing of mutations in pfcrt 72-76 was done for a set of randomly selected resistant isolates. Four microsatellite (MS) markers were analysed to determine the heterozygosity. Results: Although CQ was withdrawn for more than a decade, 100% of the parasites still carried the pfcrt K76T mutation. All isolates were mutant at the K76T polymorphism. Based on combinations of MS markers, seven different Ethiopian CQR variants (E1-E7) were identified. Heterozygosity (He) for MS flanking the pfcrt chloroquine resistance allele ranged from 0.00 (mscrt -29, -29.268 kb) to 0.21 (mscrt -2, -2.814 kb). H-e ranged from 0.00 (msint 3, 0 kb) to 0.19 (msint 2, 0 kb) for MS within the pfcrt gene. Both intronic and MS flanking the pfcrt gene showed low levels of diversity. Conclusion: pfcrt CQR allele seems to be fixed in the study area. Of the different haplotypes associated with CQR, only the CVIET genotype was identified. No reversal to the wild-type has occurred in Ethiopia unlike in many Africa countries where CQR parasites declined after cessation of CQ use. Decreased diversity in CQR isolates surrounding pfcrt suggests CQ selection and homogenization among CQR parasite population. While mutation in msint 3 and mscrt -29 of the mutant pfcrt allele is being fixed, it seems that mutations in msint 2 and mscrt -2 are still evolving and may indicate the start of re-diversification of the population from a fixed 76 T population.

Keywords
pfcrt, Wild type, Drug resistance, Chloroquine, Plasmodium falciparum, Mutations, Heterozygosity, Microsatellite, Ethiopia
National Category
Infectious Medicine
Identifiers
urn:nbn:se:uu:diva-225094 (URN)10.1186/1475-2875-13-120 (DOI)000334807900004 ()
Note

Golassa and Enweji contributed equally to this work.

Available from: 2014-05-27 Created: 2014-05-27 Last updated: 2017-12-05Bibliographically approved
Mongella, S., Enweji, N., Mnongone, N., Minde, M., Kamugisha, E. & Swedberg, G. (2014). High prevalence of Plasmodium falciparum pfcrt K76T mutation in children with sickle cell disease at a tertiary hospital in north-western Tanzania. Tanzania Journal of Health Research, 16(4)
Open this publication in new window or tab >>High prevalence of Plasmodium falciparum pfcrt K76T mutation in children with sickle cell disease at a tertiary hospital in north-western Tanzania
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2014 (English)In: Tanzania Journal of Health Research, ISSN 1821-6404, Vol. 16, no 4Article in journal (Refereed) Published
Abstract [en]

The high prevalence of sickle cell disease (SCD) and trait in Sub-Saharan Africa coincides with thedistribution of Plasmodium falciparum malaria. Due to prolonged heavy use of chloroquine (CQ) as anantimalarial, drug resistance has developed. Many countries including Tanzania abandoned the use of CQfor uncomplicated malaria, except its use as prophylaxis in patients with sickle cell disease. This studyinvestigated the prevalence of malaria in SCD patients and mutations associated with CQ resistance.Children diagnosed with sickle cell disease attending both outpatient clinic and those admitted at BugandoMedical Centre in north-western Tanzania were screened for malaria using thick blood smear. A driedblood spot on Whatman filter paper was also taken for polymerase chain reaction (PCR) and restrictionfragment length polymorphism. Among 123 known patients with sickle cell disease, the prevalence ofmalaria by blood smear microscopy was 3.2% and by PCR was 13.8%. The prevalence of K76T mutationamong the patients was 81.3%. The majority of the patients (72.4%) were using chloroquine prophylaxis. Inconclusion, the prevalence of malaria parasitaemia among children with sickle cell disease attending BMC islow (3.2%) by microscopy but several children maintain sub patent infection detectable by PCR. Theprevalence of chloroquine resistant P. falciparum in these children was higher than that previously seen innormal population in Tanzania. We recommend special attention to be paid to patients with sickle celldisease while studying the dynamics of drug resistant parasites.

National Category
Clinical Medicine
Identifiers
urn:nbn:se:uu:diva-235231 (URN)10.4314/thrb.v16i4.1 (DOI)
Available from: 2014-10-29 Created: 2014-10-29 Last updated: 2017-12-05Bibliographically approved
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