Hantavirus protein interactions regulate cellular functions and signaling responses

Klingström, Jonas; Ahlm, Clas

doi:10.1586/eri.10.157

Cited by 12 publications

(14 citation statements)

References 170 publications

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“…The human adenovirus type 5 encoded Ad5-100K specifically inhibits granzyme B, whereas the poxvirus CrmA inhibits granzyme B, caspase 3 and other caspases [20], [22]–[24], [29]. Adenovirus and poxvirus are DNA-viruses expressing 20 to 200 viral proteins; in contrast hantaviruses are small RNA viruses encoding only four structural proteins [5]. In this regard, it is striking that hantaviruses harbor such a specific viral evasion strategy.…”

Section: Discussionmentioning

confidence: 99%

Hantavirus-infection Confers Resistance to Cytotoxic Lymphocyte-Mediated Apoptosis

et al. 2013

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Hantaviruses cause hemorrhagic fever with renal syndrome (HFRS) and hantavirus cardio-pulmonary syndrome (HCPS; also called hantavirus pulmonary syndrome (HPS)), both human diseases with high case-fatality rates. Endothelial cells are the main targets for hantaviruses. An intriguing observation in patients with HFRS and HCPS is that on one hand the virus infection leads to strong activation of CD8 T cells and NK cells, on the other hand no obvious destruction of infected endothelial cells is observed. Here, we provide an explanation for this dichotomy by showing that hantavirus-infected endothelial cells are protected from cytotoxic lymphocyte-mediated induction of apoptosis. When dissecting potential mechanisms behind this phenomenon, we discovered that the hantavirus nucleocapsid protein inhibits the enzymatic activity of both granzyme B and caspase 3. This provides a tentative explanation for the hantavirus-mediated block of cytotoxic granule-mediated apoptosis-induction, and hence the protection of infected cells from cytotoxic lymphocytes. These findings may explain why infected endothelial cells in hantavirus-infected patients are not destroyed by the strong cytotoxic lymphocyte response.

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Section: Discussionmentioning

confidence: 99%

Hantavirus-infection Confers Resistance to Cytotoxic Lymphocyte-Mediated Apoptosis

et al. 2013

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“…In vitro -studies performed in human cells have shown that hantaviruses can interfere with several signalling pathways that are involved in innate immune activation and function [9], but it is still unknown if these effects are different from those in the natural hosts. Investigation and comparison of the mechanisms by which hantaviruses affect human and natural host cells is important in order to better understand why hantaviruses cause disease in man and also how they establish a chronic infection in their natural hosts.…”

Section: Discussionmentioning

confidence: 99%

“…Currently no specific treatment or US FDA-approved vaccines are available against HFRS/HCPS. While it has been shown that hantaviruses can deregulate human endothelial cell functions [7], activate unusual immune responses in patients [2], [8], and interfere with several signaling pathways in human cells [9] the exact mechanism of symptoms associated with HFRS/HCPS still remains unknown. Interestingly, while hantaviruses cause a transient infection and disease in humans, infections of the natural rodent hosts seem to be chronic and asymptomatic.…”

Section: Introductionmentioning

confidence: 99%

A Model System for In Vitro Studies of Bank Vole Borne Viruses

et al. 2011

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The bank vole (Myodes glareolus) is a common small mammal in Europe and a natural host for several important emerging zoonotic viruses, e.g. Puumala hantavirus (PUUV) that causes hemorrhagic fever with renal syndrome (HFRS). Hantaviruses are known to interfere with several signaling pathways in infected human cells, and HFRS is considered an immune-mediated disease. There is no in vitro-model available for infectious experiments in bank vole cells, nor tools for analyses of bank vole immune activation and responses. Consequently, it is not known if there are any differences in the regulation of virus induced responses in humans compared to natural hosts during infection. We here present an in vitro-model for studies of bank vole borne viruses and their interactions with natural host cell innate immune responses. Bank vole embryonic fibroblasts (VEFs) were isolated and shown to be susceptible for PUUV-infection, including a wild-type PUUV strain (only passaged in bank voles). The significance of VEFs as a model system for bank vole associated viruses was further established by infection studies showing that these cells are also susceptible to tick borne encephalitis, cowpox and Ljungan virus. The genes encoding bank vole IFN-β and Mx2 were partially sequenced and protocols for semi-quantitative RT-PCR were developed. Interestingly, PUUV did not induce an increased IFN-β or Mx2 mRNA expression. Corresponding infections with CPXV and LV induced IFN-β but not Mx2, while TBEV induced both IFN-β and Mx2.In conclusion, VEFs together with protocols developed for detection of bank vole innate immune activation provide valuable tools for future studies of how PUUV and other zoonotic viruses affect cells derived from bank voles compared to human cells. Notably, wild-type PUUV which has been difficult to cultivate in vitro readily infected VEFs, suggesting that embryonic fibroblasts from natural hosts might be valuable for isolation of wild-type hantaviruses.

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“…In infected humans, hantaviruses mainly target vascular endothelial cells, but they also infect epithelial cells, mononuclear phagocytes (MNP), follicular dendritic cells (DC) and likely also other types of cells . Although hantaviruses affect several cellular functions, infection with hantaviruses is not cytopathic per se .…”

Section: Introductionmentioning

confidence: 99%

Innate and adaptive immune responses against human Puumala virus infection: immunopathogenesis and suggestions for novel treatment strategies for severe hantavirus‐associated syndromes

et al. 2019

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Klingstr€ om J, Smed-S€ orensen A, Maleki KT, Sol a-Riera C, Ahlm C, Bj€ orkstr€ om NK, Ljunggren HG (Karolinska University Hospital, Stockholm, Sweden; Ume a University, Ume a, Sweden). Innate and adaptive immune responses against human Puumala virus infection: immunopathogenesis and suggestions for novel treatment strategies for severe hantavirus-associated syndromes (Key Symposium). J Intern Med 2019; 285: 510-523. latter conditions may also be applicable in severe hantavirus infections. Immune responses to Puumala virus infection / J. Klingstr € om et al.

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Hantavirus protein interactions regulate cellular functions and signaling responses

Cited by 12 publications

References 170 publications

Hantavirus-infection Confers Resistance to Cytotoxic Lymphocyte-Mediated Apoptosis

Hantavirus-infection Confers Resistance to Cytotoxic Lymphocyte-Mediated Apoptosis

A Model System for In Vitro Studies of Bank Vole Borne Viruses

Innate and adaptive immune responses against human Puumala virus infection: immunopathogenesis and suggestions for novel treatment strategies for severe hantavirus‐associated syndromes

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