The Exonuclease Domain of Lassa Virus Nucleoprotein Is Involved in Antigen-Presenting-Cell-Mediated NK Cell Responses

Russier, Marion; Reynard, Stéphanie; Carnec, Xavier; Baize, Sylvain

doi:10.1128/jvi.01908-14

Cited by 23 publications

(19 citation statements)

References 34 publications

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“…Our findings are supported by recent studies with recombinant LASV carrying the NP catalytic double mutations (D389T/G392A and D389A/G392A), which lose the ability to suppress the type I IFN-induction pathway in dendritic cells or macrophages, which are thought to be primary target cells for virus infection [ 6 , 7 ]. The inability of the LASV NP catalytic mutants to suppress type I IFNs results in upregulated expression levels of major histocompatibility complex (MHC) class I gene pathways as well as important macrophage-derived cytokines that activate natural killer (NK) cells to participate in the direct killing of the infected cells.…”

supporting

confidence: 85%

Immunosuppressive arenaviral exoribonuclease

Meyer

2015

Oncotarget

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supporting

confidence: 85%

Immunosuppressive arenaviral exoribonuclease

Meyer

2015

Oncotarget

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“…The Lassa virus nucleoprotein (NP) has the capacity to block IFN induction which involves, at least in part, NP 3’-5’ exonuclease activity [85-87]. Lassa virus NP is also involved in the inhibition of antigen-presenting cell (DC and macrophage)-mediated NK cell responses [88]. It has also been shown that the LASV Z protein can inhibit RIG-I and Melanoma Differentiation-Associated protein 5 (MDA5) [89,90].…”

Section: Similarities Of Other Vhfs To Ebola Virusmentioning

confidence: 99%

Molecular pathogenesis of viral hemorrhagic fever

Basler

2017

Semin Immunopathol

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The clinical syndrome referred to as viral hemorrhagic fever (VHF) can be caused by several different families of RNA viruses, including select members of the arenaviruses, bunyaviruses, filoviruses, and flaviviruses. VHF is characterized by malaise, fever, vascular permeability, decreased plasma volume, coagulation abnormalities, and varying degrees of hemorrhage. Study of the filovirus Ebola virus has demonstrated a critical role for suppression of innate antiviral defenses in viral pathogenesis. Additionally, antigen-presenting cells are targets of productive infection and immune dysregulation. Among these cell populations, monocytes and macrophages are proposed to produce damaging inflammatory cytokines, while infected dendritic cells fail to undergo proper maturation, potentially impairing adaptive immunity. Uncontrolled virus replication and accompanying inflammatory responses are thought to promote vascular leakage and coagulopathy. However, the specific molecular pathways that underlie these features of VHF remain poorly understood. The arenavirus Lassa virus and the flavivirus yellow fever virus exhibit similar molecular pathogenesis suggesting common underlying mechanisms. Because non-human primate models that closely mimic VHF are available for Ebola, Lassa, and yellow fever viruses, we propose that comparative molecular studies using these models will yield new insights into the molecular underpinnings of VHF and suggest new therapeutic approaches.

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“…Interestingly, outside the order Nidovirales, the only other known RNA virusencoded 3=-to-5= exoribonucleases are found in the Arenaviridae family of viruses. Lassa fever virus nucleoprotein ExoN is not thought to participate in fidelity regulation; rather, it participates in immune evasion by degrading dsRNA and thereby prevents antigen-presenting cell-mediated NK cell activation (18)(19)(20). Recently, in the Alphacoronavirus transmissible gastroenteritis virus (TGEV), a mutation in the nsp14 ExoN zinc finger was shown to generate lower levels of dsRNA than wild-type (WT) TGEV.…”

mentioning

confidence: 99%

Murine Hepatitis Virus nsp14 Exoribonuclease Activity Is Required for Resistance to Innate Immunity

Case

Elliott

et al. 2018

J Virol

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Coronaviruses (CoVs) are positive-sense RNA viruses that infect numerous mammalian and avian species and are capable of causing severe and lethal disease in humans. CoVs encode several innate immune antagonists that counteract the host innate immune response to facilitate efficient viral replication. CoV nonstructural protein 14 (nsp14) encodes 3'-to-5' exoribonuclease activity (ExoN), which performs a proofreading function and is required for high-fidelity replication. Outside of the order , arenaviruses are the only RNA viruses that encode an ExoN, which functions to degrade double-stranded RNA (dsRNA) replication intermediates. In this study, we tested the hypothesis that CoV ExoN also functions to antagonize the innate immune response. We demonstrate that viruses lacking ExoN activity [ExoN(-)] are sensitive to cellular pretreatment with interferon beta (IFN-β) in a dose-dependent manner. In addition, ExoN(-) virus replication was attenuated in wild-type bone marrow-derived macrophages (BMMs) and partially restored in interferon alpha/beta receptor-deficient (IFNAR) BMMs. ExoN(-) virus replication did not result in IFN-β gene expression, and in the presence of an IFN-β-mediated antiviral state, ExoN(-) viral RNA levels were not substantially reduced relative to those of untreated samples. However, ExoN(-) virus generated from IFN-β-pretreated cells had reduced specific infectivity and decreased relative fitness, suggesting that ExoN(-) virus generated during an antiviral state is less viable to establish a subsequent infection. Overall, our data suggest murine hepatitis virus (MHV) ExoN activity is required for resistance to the innate immune response, and antiviral mechanisms affecting the viral RNA sequence and/or an RNA modification act on viruses lacking ExoN activity. CoVs encode multiple antagonists that prevent or disrupt an efficient innate immune response. Additionally, no specific antiviral therapies or vaccines currently exist for human CoV infections. Therefore, the study of CoV innate immune antagonists is essential for understanding how CoVs overcome host defenses and to maximize potential therapeutic interventions. Here, we sought to determine the contributions of nsp14 ExoN activity in the induction of and resistance to the innate immune response. We show that viruses lacking nsp14 ExoN activity are more sensitive than wild-type MHV to restriction by exogenous IFN-β and that viruses produced in the presence of an antiviral state are less capable of establishing a subsequent viral infection. Our results support the hypothesis that murine hepatitis virus ExoN activity is required for resistance to the innate immune response.

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The Exonuclease Domain of Lassa Virus Nucleoprotein Is Involved in Antigen-Presenting-Cell-Mediated NK Cell Responses

Abstract: Lassa virus is an Old World

Cited by 23 publications

References 34 publications

Immunosuppressive arenaviral exoribonuclease

Immunosuppressive arenaviral exoribonuclease

Molecular pathogenesis of viral hemorrhagic fever

Murine Hepatitis Virus nsp14 Exoribonuclease Activity Is Required for Resistance to Innate Immunity

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