Exonuclease Domain of the Lassa Virus Nucleoprotein Is Critical To Avoid RIG-I Signaling and To Inhibit the Innate Immune Response

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

doi:10.1128/jvi.01923-14

Cited by 47 publications

(42 citation statements)

References 23 publications

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“…served that rNP-LASV-infected DC and M are activated in that costimulatory molecules are upregulated and cytokines and chemokines are released (35). The NK cell activation that we report here is thus consistent with an activated phenotype of APC induced by rNP-LASV.…”

Section: Discussionsupporting

confidence: 74%

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

Russier

Reynard

Carnec

et al. 2014

J Virol

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Section: Discussionsupporting

confidence: 74%

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

Russier

Reynard

Carnec

et al. 2014

J Virol

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“…Lassa virus infection does not activate DCs or macrophages and Lassa virus-infected DCs fail to stimulate strong T cell responses and only induce weak memory responses [25,82,84]. 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].…”

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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“…This anti-IFN activity of arenavirus NP has been attributed to a recently identified 3=-5= exoribonuclease domain in the C terminus of NP, which is thought to digest double-stranded RNA (dsRNA) substrates formed during viral replication in an attempt to mask infection from cellular detection (56)(57)(58)(59)(60). Thus, we evaluated whether reduced protein expression levels would affect the abilities of different NP chimeras to inhibit SeV-mediated activation of an IFN-␤ promoter (42)(43)(44).…”

Section: Effect Of CD On Lcmv Np Expression and Functionmentioning

confidence: 99%

Development of Live-Attenuated Arenavirus Vaccines Based on Codon Deoptimization

Cheng

Ortiz-Riaño

Nogales

et al. 2015

J Virol

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Arenaviruses have a significant impact on public health and pose a credible biodefense threat, but the development of safe and effective arenavirus vaccines has remained elusive, and currently, no Food and Drug Administration (FDA)-licensed arenavirus vaccines are available. Here, we explored the use of a codon deoptimization (CD)-based approach as a novel strategy to develop live-attenuated arenavirus vaccines. We recoded the nucleoprotein (NP) of the prototypic arenavirus lymphocytic choriomeningitis virus (LCMV) with the least frequently used codons in mammalian cells, which caused lower LCMV NP expression levels in transfected cells that correlated with decreased NP activity in cell-based functional assays. We used reverse-genetics approaches to rescue a battery of recombinant LCMVs (rLCMVs) encoding CD NPs (rLCMV/NP CD ) that showed attenuated growth kinetics in vitro. Moreover, experiments using the well-characterized mouse model of LCMV infection revealed that rLCMV/NP CD1 and rLCMV/NP CD2 were highly attenuated in vivo but, upon a single immunization, conferred complete protection against a subsequent lethal challenge with wild-type (WT) recombinant LCMV (rLCMV/WT). Both rLCMV/NP CD1 and rLCMV/NP CD2 were genetically and phenotypically stable during serial passages in FDA vaccine-approved Vero cells. These results provide proof of concept of the safety, efficacy, and stability of a CD-based approach for developing live-attenuated vaccine candidates against human-pathogenic arenaviruses. IMPORTANCESeveral arenaviruses cause severe hemorrhagic fever in humans and pose a credible bioterrorism threat. Currently, no FDA-licensed vaccines are available to combat arenavirus infections, while antiarenaviral therapy is limited to the off-label use of ribavirin, which is only partially effective and is associated with side effects. Here, we describe the generation of recombinant versions of the prototypic arenavirus LCMV encoding codon-deoptimized viral nucleoproteins (rLCMV/NP CD ). We identified rLCMV/NP CD1 and rLCMV/ NP CD2 to be highly attenuated in vivo but able to confer protection against a subsequent lethal challenge with wild-type LCMV. These viruses displayed an attenuated phenotype during serial amplification passages in cultured cells. Our findings support the use of this approach for the development of safe, stable, and protective live-attenuated arenavirus vaccines.A renaviruses cause chronic infections of rodents across the world, and human infections occur through mucosal exposure to aerosols or by direct contact of abraded skin with infectious materials (1). Several arenaviruses, chiefly Lassa virus (LASV), the causative agent of Lassa fever (LF) in West Africa, and Junín virus (JUNV), the causative agent of Argentine hemorrhagic fever (AHF) in Argentina, cause hemorrhagic fever (HF) disease in humans that is associated with high morbidity and significant mortality and pose important public health problems in their areas of endemicity (1-3). Notably, increased travel has led to the import...

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Exonuclease Domain of the Lassa Virus Nucleoprotein Is Critical To Avoid RIG-I Signaling and To Inhibit the Innate Immune Response

Cited by 47 publications

References 23 publications

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

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

Molecular pathogenesis of viral hemorrhagic fever

Development of Live-Attenuated Arenavirus Vaccines Based on Codon Deoptimization

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