Lassa Virus, but Not Highly Pathogenic New World Arenaviruses, Restricts Immunostimulatory Double-Stranded RNA Accumulation during Infection.
Arenaviridae Infections
/ virology
Arenavirus
/ genetics
Arenaviruses, New World
/ immunology
Cell Line
Host-Pathogen Interactions
Humans
Immunity, Innate
Interferon Type I
/ metabolism
Junin virus
/ immunology
Lassa Fever
/ immunology
Lassa virus
/ immunology
Nucleoproteins
/ metabolism
RNA, Double-Stranded
/ immunology
Virus Replication
eIF-2 Kinase
/ metabolism
Junín virus
Lassa virus
Machupo virus
PKR
RIG-I
arenavirus
dsRNA
hemorrhagic fever-causing virus
innate immune
pathogen-associated molecular patterns
Journal
Journal of virology
ISSN: 1098-5514
Titre abrégé: J Virol
Pays: United States
ID NLM: 0113724
Informations de publication
Date de publication:
16 04 2020
16 04 2020
Historique:
received:
26
11
2019
accepted:
09
02
2020
pubmed:
14
2
2020
medline:
21
10
2020
entrez:
14
2
2020
Statut:
epublish
Résumé
The arenaviruses Lassa virus (LASV), Junín virus (JUNV), and Machupo virus (MACV) can cause severe and fatal diseases in humans. Although these pathogens are closely related, the host immune responses to these virus infections differ remarkably, with direct implications for viral pathogenesis. LASV infection is immunosuppressive, with a very low-level interferon response. In contrast, JUNV and MACV infections stimulate a robust interferon (IFN) response in a retinoic acid-inducible gene I (RIG-I)-dependent manner and readily activate protein kinase R (PKR), a known host double-stranded RNA (dsRNA) sensor. In response to infection with RNA viruses, host nonself RNA sensors recognize virus-derived dsRNA as danger signals and initiate innate immune responses. Arenavirus nucleoproteins (NPs) contain a highly conserved exoribonuclease (ExoN) motif, through which LASV NP has been shown to degrade virus-derived immunostimulatory dsRNA in biochemical assays. In this study, we for the first time present evidence that LASV restricts dsRNA accumulation during infection. Although JUNV and MACV NPs also have the ExoN motif, dsRNA readily accumulated in infected cells and often colocalized with dsRNA sensors. Moreover, LASV coinfection diminished the accumulation of dsRNA and the IFN response in JUNV-infected cells. The disruption of LASV NP ExoN with a mutation led to dsRNA accumulation and impaired LASV replication in minigenome systems. Importantly, both LASV NP and RNA polymerase L protein were required to diminish the accumulation of dsRNA and the IFN response in JUNV infection. For the first time, we discovered a collaboration between LASV NP ExoN and L protein in limiting dsRNA accumulation. Our new findings provide mechanistic insights into the differential host innate immune responses to highly pathogenic arenavirus infections.
Identifiants
pubmed: 32051278
pii: JVI.02006-19
doi: 10.1128/JVI.02006-19
pmc: PMC7163147
pii:
doi:
Substances chimiques
Interferon Type I
0
Nucleoproteins
0
RNA, Double-Stranded
0
eIF-2 Kinase
EC 2.7.11.1
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : NIAID NIH HHS
ID : R01 AI129198
Pays : United States
Organisme : NIAID NIH HHS
ID : T32 AI007526
Pays : United States
Informations de copyright
Copyright © 2020 American Society for Microbiology.
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