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

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...

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Autores principales:	Kathryn McGuckin Wuertz, Piper M Treuting, Emily A Hemann, Katharina Esser-Nobis, Annelise G Snyder, Jessica B Graham, Brian P Daniels, Courtney Wilkins, Jessica M Snyder, Kathleen M Voss, Andrew Oberst, Jennifer Lund, Michael Gale
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2019
Materias:	Immunologic diseases. Allergy RC581-607 Biology (General) QH301-705.5
Acceso en línea:	https://doaj.org/article/5b1fd2c0b9da4919aee0c9299e0572e0
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spelling	oai:doaj.org-article:5b1fd2c0b9da4919aee0c9299e0572e02021-12-02T20:00:19ZSTING is required for host defense against neuropathological West Nile virus infection.1553-73661553-737410.1371/journal.ppat.1007899https://doaj.org/article/5b1fd2c0b9da4919aee0c9299e0572e02019-08-01T00:00:00Zhttps://doi.org/10.1371/journal.ppat.1007899https://doaj.org/toc/1553-7366https://doaj.org/toc/1553-7374West 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.Kathryn McGuckin WuertzPiper M TreutingEmily A HemannKatharina Esser-NobisAnnelise G SnyderJessica B GrahamBrian P DanielsCourtney WilkinsJessica M SnyderKathleen M VossAndrew OberstJennifer LundMichael GalePublic Library of Science (PLoS)articleImmunologic diseases. AllergyRC581-607Biology (General)QH301-705.5ENPLoS Pathogens, Vol 15, Iss 8, p e1007899 (2019)
institution	DOAJ
collection	DOAJ
language	EN
topic	Immunologic diseases. Allergy RC581-607 Biology (General) QH301-705.5
spellingShingle	Immunologic diseases. Allergy RC581-607 Biology (General) QH301-705.5 Kathryn McGuckin Wuertz Piper M Treuting Emily A Hemann Katharina Esser-Nobis Annelise G Snyder Jessica B Graham Brian P Daniels Courtney Wilkins Jessica M Snyder Kathleen M Voss Andrew Oberst Jennifer Lund Michael Gale STING is required for host defense against neuropathological West Nile virus infection.
description	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.
format	article
author	Kathryn McGuckin Wuertz Piper M Treuting Emily A Hemann Katharina Esser-Nobis Annelise G Snyder Jessica B Graham Brian P Daniels Courtney Wilkins Jessica M Snyder Kathleen M Voss Andrew Oberst Jennifer Lund Michael Gale
author_facet	Kathryn McGuckin Wuertz Piper M Treuting Emily A Hemann Katharina Esser-Nobis Annelise G Snyder Jessica B Graham Brian P Daniels Courtney Wilkins Jessica M Snyder Kathleen M Voss Andrew Oberst Jennifer Lund Michael Gale
author_sort	Kathryn McGuckin Wuertz
title	STING is required for host defense against neuropathological West Nile virus infection.
title_short	STING is required for host defense against neuropathological West Nile virus infection.
title_full	STING is required for host defense against neuropathological West Nile virus infection.
title_fullStr	STING is required for host defense against neuropathological West Nile virus infection.
title_full_unstemmed	STING is required for host defense against neuropathological West Nile virus infection.
title_sort	sting is required for host defense against neuropathological west nile virus infection.
publisher	Public Library of Science (PLoS)
publishDate	2019
url	https://doaj.org/article/5b1fd2c0b9da4919aee0c9299e0572e0
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STING is required for host defense against neuropathological West Nile virus infection.

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