Format

Send to

Choose Destination
PLoS Pathog. 2019 Aug 15;15(8):e1007899. doi: 10.1371/journal.ppat.1007899. eCollection 2019 Aug.

STING is required for host defense against neuropathological West Nile virus infection.

Author information

1
Department of Global Health, University of Washington, Seattle, WA, United States of America.
2
Department of Immunology, University of Washington, Seattle, WA, United States of America.
3
Center for Innate Immunity and Immune Disease, University of Washington, Seattle, WA, United States of America.
4
Department of Defense; United States Army Medical Department, San Antonio, TX, United States of America.
5
Department of Comparative Medicine, University of Washington, Seattle, WA, United States of America.
6
Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, WA, United States of America.
7
Department of Cell Biology and Neuroscience, Rutgers University, Piscataway, NJ, United States of America.

Abstract

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.

Supplemental Content

Full text links

Icon for Public Library of Science Icon for PubMed Central
Loading ...
Support Center