STING is required for host defense against neuropathological West Nile virus infection.
Journal
PLoS pathogens
ISSN: 1553-7374
Titre abrégé: PLoS Pathog
Pays: United States
ID NLM: 101238921
Informations de publication
Date de publication:
08 2019
08 2019
Historique:
received:
08
02
2019
accepted:
07
06
2019
entrez:
16
8
2019
pubmed:
16
8
2019
medline:
16
1
2020
Statut:
epublish
Résumé
West Nile Virus (WNV), an emerging and re-emerging RNA virus, is the leading source of arboviral encephalitic morbidity and mortality in the United States. WNV infections are acutely controlled by innate immunity in peripheral tissues outside of the central nervous system (CNS) but WNV can evade the actions of interferon (IFN) to facilitate CNS invasion, causing encephalitis, encephalomyelitis, and death. Recent studies indicate that STimulator of INterferon Gene (STING), canonically known for initiating a type I IFN production and innate immune response to cytosolic DNA, is required for host defense against neurotropic RNA viruses. We evaluated the role of STING in host defense to control WNV infection and pathology in a murine model of infection. When challenged with WNV, STING knock out (-/-) mice displayed increased morbidity and mortality compared to wild type (WT) mice. Virologic analysis and assessment of STING activation revealed that STING signaling was not required for control of WNV in the spleen nor was WNV sufficient to mediate canonical STING activation in vitro. However, STING-/- mice exhibited a clear trend of increased viral load and virus dissemination in the CNS. We found that STING-/- mice exhibited increased and prolonged neurological signs compared to WT mice. Pathological examination revealed increased lesions, mononuclear cellular infiltration and neuronal death in the CNS of STING-/- mice, with sustained pathology after viral clearance. We found that STING was required in bone marrow derived macrophages for early control of WNV replication and innate immune activation. In vivo, STING-/- mice developed an aberrant T cell response in both the spleen and brain during WNV infection that linked with increased and sustained CNS pathology compared to WT mice. Our findings demonstrate that STING plays a critical role in immune programming for the control of neurotropic WNV infection and CNS disease.
Identifiants
pubmed: 31415679
doi: 10.1371/journal.ppat.1007899
pii: PPATHOGENS-D-19-00259
pmc: PMC6695101
doi:
Substances chimiques
Membrane Proteins
0
Sting1 protein, mouse
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, U.S. Gov't, Non-P.H.S.
Langues
eng
Sous-ensembles de citation
IM
Pagination
e1007899Subventions
Organisme : NIH HHS
ID : P51 OD010425
Pays : United States
Organisme : NIGMS NIH HHS
ID : T32 GM007270
Pays : United States
Organisme : NIAID NIH HHS
ID : U19 AI100625
Pays : United States
Organisme : NIAID NIH HHS
ID : R01 AI132595
Pays : United States
Organisme : NIAID NIH HHS
ID : U19 AI083019
Pays : United States
Déclaration de conflit d'intérêts
The authors have declared that no competing interests exist.
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