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Svensson, Catharina
Publications (10 of 20) Show all publications
Schubert, E., Mun, K., Larsson, M., Panagiotou, S., Idevall Hagren, O., Svensson, C. & Punga, T. (2024). Complex regulation of mitochondrial signaling by human adenovirus minor capsid protein VI. Journal of Virology, 98(7), Article ID e00356-24.
Open this publication in new window or tab >>Complex regulation of mitochondrial signaling by human adenovirus minor capsid protein VI
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2024 (English)In: Journal of Virology, ISSN 0022-538X, E-ISSN 1098-5514, Vol. 98, no 7, article id e00356-24Article in journal (Refereed) Published
Abstract [en]

The controlled release of mitochondrial content into the cytosol has emerged as one of the key steps in mitochondrial signaling. In particular, the release of mitochondrial DNA (mtDNA) into the cytosol has been shown to activate interferon beta (IFN-beta) gene expression to execute the innate immune response. In this report, we show that human adenovirus type 5 (HAdV-C5) infection induces the release of mtDNA into the cytosol. The release of mtDNA is mediated by the viral minor capsid protein VI (pVI), which localizes to mitochondria. The presence of the mitochondrial membrane proteins Bak and Bax are needed for the mtDNA release, whereas the viral E1B-19K protein blocked pVI-mediated mtDNA release. Surprisingly, the pVI-mediated mtDNA release did not increase but inhibited the IFN-beta gene expression. Notably, the pVI expression caused mitochondrial leakage of the HSP60 protein. The latter prevented specific phosphorylation of the interferon regulatory factor 3 (IRF3) needed for IFN-beta gene expression. Overall, we assign a new mitochondria and IFN-beta signaling-modulating function to the HAdV-C5 minor capsid protein VI.IMPORTANCEHuman adenoviruses (HAdVs) are common pathogens causing various self-limiting diseases, including conjunctivitis and the common cold. HAdVs need to interfere with multiple cellular signaling pathways during the infection to gain control over the host cell. In this study, we identified human adenovirus type 5 (HAdV-C5) minor capsid protein VI as a factor modulating mitochondrial membrane integrity and mitochondrial signaling. We show that pVI-altered mitochondrial signaling impedes the cell's innate immune response, which may benefit HAdV growth. Overall, our study provides new detailed insights into the HAdV-mitochondria interactions and signaling. This knowledge is helpful when developing new anti-viral treatments against pathogenic HAdV infections and improving HAdV-based therapeutics. Human adenoviruses (HAdVs) are common pathogens causing various self-limiting diseases, including conjunctivitis and the common cold. HAdVs need to interfere with multiple cellular signaling pathways during the infection to gain control over the host cell. In this study, we identified human adenovirus type 5 (HAdV-C5) minor capsid protein VI as a factor modulating mitochondrial membrane integrity and mitochondrial signaling. We show that pVI-altered mitochondrial signaling impedes the cell's innate immune response, which may benefit HAdV growth. Overall, our study provides new detailed insights into the HAdV-mitochondria interactions and signaling. This knowledge is helpful when developing new anti-viral treatments against pathogenic HAdV infections and improving HAdV-based therapeutics.

Place, publisher, year, edition, pages
American Society for Microbiology, 2024
Keywords
adenovirus, mitochondria, immune system, cGAS
National Category
Microbiology in the medical area
Identifiers
urn:nbn:se:uu:diva-537757 (URN)10.1128/jvi.00356-24 (DOI)001274917400062 ()38837380 (PubMedID)
Funder
Swedish Cancer Society, 180599Swedish Cancer Society, 211537Knut and Alice Wallenberg Foundation, KAW 2017.0071
Available from: 2024-09-18 Created: 2024-09-18 Last updated: 2024-09-18Bibliographically approved
Hajikhezri, Z., Kaira, Y., Schubert, E., Darweesh, M., Svensson, C., Akusjärvi, G. & Punga, T. (2023). Fragile X-Related Protein FXR1 Controls Human Adenovirus Capsid mRNA Metabolism. Journal of Virology, 97(2), Article ID e0153922.
Open this publication in new window or tab >>Fragile X-Related Protein FXR1 Controls Human Adenovirus Capsid mRNA Metabolism
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2023 (English)In: Journal of Virology, ISSN 0022-538X, E-ISSN 1098-5514, Vol. 97, no 2, article id e0153922Article in journal (Refereed) Published
Abstract [en]

Human adenoviruses (HAdVs) are widespread pathogens causing a variety of diseases. A well-controlled expression of virus capsid mRNAs originating from the major late transcription unit (MLTU) is essential for forming the infectious virus progeny. However, regulation of the MLTU mRNA metabolism has mainly remained enigmatic. In this study, we show that the cellular RNA-binding protein FXR1 controls the stability of the HAdV-5 MLTU mRNAs, as depletion of FXR1 resulted in increased steady-state levels of MLTU mRNAs. Surprisingly, the lack of FXR1 reduced viral capsid protein accumulation and formation of the infectious virus progeny, indicating an opposing function of FXR1 in HAdV-5 infection. Further, the long FXR1 isoform interfered with MLTU mRNA translation, suggesting FXR1 isoform-specific functions in virus-infected cells. We also show that the FXR1 protein interacts with N6-methyladenosine (m6A)-modified MLTU mRNAs, thereby acting as a novel m6A reader protein in HAdV-5 infected cells. Collectively, our study identifies FXR1 as a regulator of MLTU mRNA metabolism in the lytic HAdV-5 life cycle.

Place, publisher, year, edition, pages
American Society for Microbiology, 2023
Keywords
FXR1, adenovirus, m6A-modification, mRNA decay, mRNA translation
National Category
Microbiology in the medical area
Identifiers
urn:nbn:se:uu:diva-501605 (URN)10.1128/jvi.01539-22 (DOI)000935450500001 ()36749074 (PubMedID)
Available from: 2023-05-10 Created: 2023-05-10 Last updated: 2023-05-10Bibliographically approved
Darweesh, M., Kamel, W., Gavrilin, M. A., Akusjärvi, G. & Svensson, C. (2019). Adenovirus VA RNAI Blocks ASC Oligomerization and Inhibits NLRP3 Inflammasome Activation. Frontiers in Immunology, 10, Article ID 2791.
Open this publication in new window or tab >>Adenovirus VA RNAI Blocks ASC Oligomerization and Inhibits NLRP3 Inflammasome Activation
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2019 (English)In: Frontiers in Immunology, E-ISSN 1664-3224, Vol. 10, article id 2791Article in journal (Refereed) Published
Abstract [en]

Virus infected immune cells can rapidly respond to the invader by activating the inflammasome and as a consequence release proinflammatory cytokines and eventually die by pyroptosis. In human adenovirus-5 (Ad5) infected THP-1 cells, inhibition of NLRP3 inflammasome activation was demonstrated by a decreased secretion of HMGB1 and matured forms of caspase-1and IL-1ß. An Ad5 mutant virus defective in expression of the non-coding VA RNAI failed to inhibit the NLRP3 inflammasome and in addition displayed formation of ASC specks and increased cell lysis. Importantly, in vitro synthesized VA RNAI was able to inhibit the NLRP3 inflammasome activity in THP-1 cells in the absence of an Ad5 infection, suggesting that VA RNAI binding to PKR and blocking its function is sufficient for inhibition of the NLRP3 inflammasome. Although the inhibition of NLRP3 inflammasome activation required the phylogenetically conserved base paired tetranucleotide sequence in the central stem of VA RNAI, we demonstrate that PKR binding to VA RNAI primarily protected the apical stem, but not the tetranucleotide sequence itself. VA RNAI did not influence the interaction between PKR and NLRP3. In contrast, we describe a novel interaction between PKR and ASC and further show that VA RNAI inhibited ASC phosphorylation and oligomerization. Collectively, our results indicate a novel role for Ad5 VA RNAI as an inhibitor of NLRP3 inflammasome activation by targeting the cellular pro-inflammatory protein PKR.

Keywords
ASC, NLRP3, PKR, VA RNAI, adenovirus, inflammasome, proinflammatory cytokines
National Category
Microbiology in the medical area
Identifiers
urn:nbn:se:uu:diva-400692 (URN)10.3389/fimmu.2019.02791 (DOI)000502348800001 ()31849970 (PubMedID)
Funder
Swedish Cancer Society, 170170Swedish Cancer Society, 180599
Available from: 2020-01-02 Created: 2020-01-02 Last updated: 2024-01-17Bibliographically approved
Assadian, F., Kamel, W., Laurell, G., Svensson, C., Punga, T. & Akusjärvi, G. (2017). Expression profile of Epstein-Barr virus and human adenovirus small RNAs in tonsillar B and T lymphocytes. PLOS ONE, 12(5), Article ID e0177275.
Open this publication in new window or tab >>Expression profile of Epstein-Barr virus and human adenovirus small RNAs in tonsillar B and T lymphocytes
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2017 (English)In: PLOS ONE, E-ISSN 1932-6203, Vol. 12, no 5, article id e0177275Article in journal (Refereed) Published
Abstract [en]

We have used high-throughput small RNA sequencing to characterize viral small RNA expression in purified tonsillar B and T lymphocytes isolated from patients tested positive for Epstein-Barr virus (EBV) or human adenovirus (HAdV) infections, respectively. In the small set of patients analyzed, the expression profile of EBV and HAdV miRNAs could not distinguish between patients diagnosed with tonsillar hypertrophy or chronic/recurrent tonsillitis. The EBV miR-BART expression profile among the patients diagnosed with tonsillar diseases resembles most closely the pattern seen in EBV+ tumors (Latency II/I). The miRBARTs that appear to be absent in normal EBV infected cells are essentially all detectable in the diseased tonsillar B lymphocytes. In the EBV+ B cells we detected 44 EBV miRBARTs derived from the proposed BART precursor hairpins whereof five are not annotated in miRBase v21. One previously undetected miRNA, BART16b-5p, originates from the miR-BART16 precursor hairpin as an alternative 5 A miR-BART16 located precisely upstream of the annotated miR-BART16-5p. Further, our analysis revealed an extensive sequence variation among the EBV miRNAs with isomiRs having a constant 5 A end but alternative 3 A ends. A range of small RNAs was also detected from the terminal stem of the EBER RNAs and the 3 A part of v-snoRNA1. During a lytic HAdV infection in established cell lines the terminal stem of the viral non-coding VA RNAs are processed to highly abundant viral miRNAs (mivaRNAs). In contrast, mivaRNA expression in HAdV positive tonsillar T lymphocytes was very low. The small RNA profile further showed that the 5 A mivaRNA from VA RNAI and the 3 A mivaRNA from VA RNAII were as predicted, whereas the 3 A mivaRNA from VA RNAI showed an aberrant processing upstream of the expected Dicer cleavage site.

Place, publisher, year, edition, pages
PUBLIC LIBRARY SCIENCE, 2017
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-326234 (URN)10.1371/journal.pone.0177275 (DOI)000402062800013 ()28542273 (PubMedID)
Funder
Swedish Cancer Society, 120678, 130469
Available from: 2017-07-06 Created: 2017-07-06 Last updated: 2022-01-29Bibliographically approved
Assadian, F., Sandström, K., Bondeson, K., Laurell, G., Lidian, A., Svensson, C., . . . Punga, T. (2016). Distribution and Molecular Characterization of Human Adenovirus and Epstein-Barr Virus Infections in Tonsillar Lymphocytes Isolated from Patients Diagnosed with Tonsillar Diseases. PLOS ONE, 11(5), Article ID e0154814.
Open this publication in new window or tab >>Distribution and Molecular Characterization of Human Adenovirus and Epstein-Barr Virus Infections in Tonsillar Lymphocytes Isolated from Patients Diagnosed with Tonsillar Diseases
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2016 (English)In: PLOS ONE, E-ISSN 1932-6203, Vol. 11, no 5, article id e0154814Article in journal (Refereed) Published
Abstract [en]

Surgically removed palatine tonsils provide a conveniently accessible source of T and B lymphocytes to study the interplay between foreign pathogens and the host immune system. In this study we have characterised the distribution of human adenovirus (HAdV), Epstein-Barr virus (EBV) and human cytomegalovirus (HCMV) in purified tonsillar T and B cell-enriched fractions isolated from three patient age groups diagnosed with tonsillar hypertrophy and chronic/recurrent tonsillitis. HAdV DNA was detected in 93 out of 111 patients (84%), while EBV DNA was detected in 58 patients (52%). The most abundant adenovirus type was HAdV-5 (68%). None of the patients were positive for HCMV. Furthermore, 43 patients (39%) showed a co-infection of HAdV and EBV. The majority of young patients diagnosed with tonsillar hypertrophy were positive for HAdV, whereas all adult patients diagnosed with chronic/recurrent tonsillitis were positive for either HAdV or EBV. Most of the tonsils from patients diagnosed with either tonsillar hypertrophy or chronic/recurrent tonsillitis showed a higher HAdV DNA copy number in T compared to B cell-enriched fraction. Interestingly, in the majority of the tonsils from patients with chronic/recurrent tonsillitis HAdV DNA was detected in T cells only, whereas hypertrophic tonsils demonstrated HAdV DNA in both T and B cell-enriched fractions. In contrast, the majority of EBV positive tonsils revealed a preference for EBV DNA accumulation in the B cell-enriched fraction compared to T cell fraction irrespective of the patients' age.

National Category
Surgery Otorhinolaryngology Cancer and Oncology
Identifiers
urn:nbn:se:uu:diva-297795 (URN)10.1371/journal.pone.0154814 (DOI)000375674800050 ()27136093 (PubMedID)
Funder
Swedish Cancer Society, 12 0504Swedish Cancer Society, 13 0469Swedish Research Council, K2012-99X-21959-01-3Swedish Research Council, 2006-5038-36531-16Åke Wiberg Foundation
Note

De 2 sista författarna delar sistaförfattarskapet.

Available from: 2016-06-28 Created: 2016-06-28 Last updated: 2021-06-14Bibliographically approved
Wu, C., Cao, X., Yu, D., Huijbers, E. J. M., Essand, M., Akusjärvi, G., . . . Svensson, C. (2016). HAdV-2-suppressed growth of SV40 T antigen-transformed mouse mammary epithelial cell-induced tumours in SCID mice. Virology, 489, 44-50
Open this publication in new window or tab >>HAdV-2-suppressed growth of SV40 T antigen-transformed mouse mammary epithelial cell-induced tumours in SCID mice
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2016 (English)In: Virology, ISSN 0042-6822, E-ISSN 1096-0341, Vol. 489, p. 44-50Article in journal (Refereed) Published
Abstract [en]

Human adenovirus (HAdV) vectors are promising tools for cancer therapy, but the shortage of efficient animal models for productive HAdV infections has restricted the evaluation of systemic effects to mainly immunodeficient mice. Previously, we reported a highly efficient replication of HAdV-2 in a non-tumorigenic mouse mammary epithelial cell line, NMuMG. Here we show that HAdV-2 gene expression and progeny formation in NMuMG cells transformed with the SV40 T antigen (NMuMG-T cells) were as efficient as in the parental NMuMG cells. Injection of HAdV-2 into tumours established by NMuMG-T in SCID mice caused reduced tumour growth and signs of intratumoural lesions. HAdV-2 replicated within the NMuMG-T-established tumours, but not in interspersed host-derived tissues within the tumours. The specific infection of NMuMG-T-derived tumours was verified by the lack of viral DNA in kidney, lung or spleen although low levels of viral DNA was occasionally found in liver.

Keywords
Oncolytic adenovirus, Murine cells, Anti-tumour activity, Permissive infection, Viral replication
National Category
Infectious Medicine
Identifiers
urn:nbn:se:uu:diva-282389 (URN)10.1016/j.virol.2015.11.031 (DOI)000370892100005 ()26707269 (PubMedID)
Funder
Swedish Cancer Society
Available from: 2016-04-05 Created: 2016-04-05 Last updated: 2022-01-29Bibliographically approved
Assadian, F., Sandström, K., Laurell, G., Svensson, C., Akusjärvi, G. & Punga, T. (2015). Efficient Isolation Protocol for B and T Lymphocytes from Human Palatine Tonsils. Journal of Visualized Experiments, 105, Article ID e53374.
Open this publication in new window or tab >>Efficient Isolation Protocol for B and T Lymphocytes from Human Palatine Tonsils
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2015 (English)In: Journal of Visualized Experiments, E-ISSN 1940-087X, Vol. 105, article id e53374Article in journal (Refereed) Published
Abstract [en]

Palatine tonsils are a rich source of B and T lymphocytes. Here we provide an easy, efficient and rapid protocol to isolate B and T lymphocytes from human palatine tonsils. The method described has been specifically adapted for studies of the viral etiology of tonsil inflammation known as tonsillitis.

National Category
Microbiology in the medical area
Identifiers
urn:nbn:se:uu:diva-274679 (URN)10.3791/53374 (DOI)000368573900061 ()
Funder
Swedish Cancer Society, 11 0253, 13 0469Swedish Research Council, K2012-99X-21959-01-3 2006-5038-36531-16
Available from: 2016-01-25 Created: 2016-01-25 Last updated: 2024-01-17Bibliographically approved
Wu, C., Bai, L., Li, Z., Samuel, C. E., Akusjärvi, G. & Svensson, C. (2015). Poor growth of human adenovirus-12 compared to adenovirus-2 correlates with a failure to impair PKR activation during the late phase of infection. Virology, 475, 120-128
Open this publication in new window or tab >>Poor growth of human adenovirus-12 compared to adenovirus-2 correlates with a failure to impair PKR activation during the late phase of infection
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2015 (English)In: Virology, ISSN 0042-6822, E-ISSN 1096-0341, Vol. 475, p. 120-128Article in journal (Refereed) Published
Abstract [en]

Human adenovirus type 12 (HAdV-12) displays a relatively low virulence and slow replication in cultured human cells, which is manifested by premature death of HAdV-12-infected cells. Whereas HAdV-2 induction of IFN-beta expression was transient, HAdV-12-infected cells maintained high levels of IFN-beta expression, protein kinase R (PKR) activation and eIF-2 alpha phosphorylation throughout the infectious cycle. The importance of the IFN-inducible PKR kinase in restriction of HAdV-12 was supported by the enhanced growth of the virus following PKR knockdown in HeLa cells. Ectopic expression of HAdV-2 VA RNAI increased HAdV-12 hexon protein expression, suggesting that insufficient VA RNA expression contributes to the restricted growth of HAdV-12. Although some adenovirus species are known to persist in human lymphoid tissues, HAdV12 has so far not been found. Thus, it is possible that the inability of HAdV12 to evade the INF response may have implications for the virus to establish long-lasting or persistent infections. (C) 2014 Elsevier Inc. All rights reserved.

Keywords
Adenovirus, VA RNA, IFN, PKR, eIF2 alpha
National Category
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Identifiers
urn:nbn:se:uu:diva-245366 (URN)10.1016/j.virol.2014.11.012 (DOI)000348176500012 ()25462352 (PubMedID)
Available from: 2015-02-26 Created: 2015-02-26 Last updated: 2017-12-04Bibliographically approved
Wu, C. J., Öberg, D., Rashid, A., Gupta, R., Mignardi, M., Johansson, S., . . . Svensson, C. (2013). A mouse mammary epithelial cell line permissive for highly efficient human adenovirus growth. Virology, 435(2), 363-371
Open this publication in new window or tab >>A mouse mammary epithelial cell line permissive for highly efficient human adenovirus growth
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2013 (English)In: Virology, ISSN 0042-6822, E-ISSN 1096-0341, Vol. 435, no 2, p. 363-371Article in journal (Refereed) Published
Abstract [en]

Although a few immunocompetent animal models to study the immune response against human adenoviruses (HAdV) are available, such as Syrian hamsters and cotton rats, HAdV replication is several logs lower compared to human control cells. We have identified a non-transformed mouse epithelial cell line (NMuMG) where HAdV-2 gene expression and progeny formation was as efficient as in the highly permissive human A549 cells. HAdV from species, D and E (HAdV-37 and HAdV-4, respectively) also caused a rapid cytopathic effect in NMuMG cells, while HAdV from species A, B1, B2 and F (HAdV-12, HAdV-3, HAdV-11 and HAdV-41, respectively) failed to do so. NMuMG cells might therefore be useful in virotherapy research and the analysis of antiviral defense mechanisms and the determination of toxicity, biodistribution and specific antitumour activity of oncolytic HAdV vectors.

National Category
Natural Sciences
Identifiers
urn:nbn:se:uu:diva-194189 (URN)10.1016/j.virol.2012.10.034 (DOI)000313459200019 ()
Available from: 2013-02-13 Created: 2013-02-11 Last updated: 2017-12-06
Zhao, H., Boije, H., Granberg, F., Pettersson, U. & Svensson, C. (2009). Activation of the interferon-induced STAT pathway during an adenovirus type 12 infection. Virology, 392(2), 186-195
Open this publication in new window or tab >>Activation of the interferon-induced STAT pathway during an adenovirus type 12 infection
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2009 (English)In: Virology, ISSN 0042-6822, E-ISSN 1096-0341, Vol. 392, no 2, p. 186-195Article in journal (Refereed) Published
Abstract [en]

We have previously described a temporal regulation of host cell gene expression during adenovirus type 2 infection (Ad2) of primary human fibroblasts. Among the eleven percent of genes deregulated by Ad2, a large fraction included genes involved in cell cycle, growth control and antiviral defense, consistent with the capacity of Ad2 to efficiently master the infected cell and cause an effectively productive infection. Adenovirus type 12 (Ad12), which belongs to the highly oncogenic subgroup, is characterised by slow progression, less cytopathic effect and lower virus yield compared to the non-oncogenic Ad2. Microarray analysis of host cell gene expression in Ad12 infected human lung fibroblasts (IMR90) demonstrated a quantitatively and qualitatively less impact on host cell gene expression, compared to Ad2. Of the relatively few genes up regulated during the course of Ad12 infection only two (5%) were identified as potential E2F targets, compared to the significant activation of E2F-dependent transcription observed during an Ad2 infection. Although approximately 30% of the genes deregulated by Ad12 were previously identified in Ad2-infected cells, a distinct difference was observed in a group of interferon-stimulated genes (ISGs). G1P2, IFI6, IFI16, IFIT1, IFIT2, IFITM1 and IRF9 were activated during the very late stage of infection, and a consistent induction of IFNbeta gene expression, preceding induction of the ISGs, was demonstrated by quantitative real-time PCR analysis. An activated JAK/STAT signalling pathway was also indicated by the accumulation of all components (STAT1, STAT2 and IRF9) of the ISGF3 transcription factor. Significantly, none of these ISGs was activated in Ad2 infected IMR90 cells. Thus, the inability of Ad12 to evade the interferon response might explain its restricted virulence.

Keywords
Adenovirus type 12, cDNA microarray, IMR90 cells, Interferon-stimulated genes (ISG)
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-119853 (URN)10.1016/j.virol.2009.07.006 (DOI)000270247300005 ()19665745 (PubMedID)
Available from: 2010-03-02 Created: 2010-03-02 Last updated: 2022-01-28Bibliographically approved
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