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Artikel ; Online: Blockade of interferon signaling decreases gut barrier integrity and promotes severe West Nile virus disease

Shih-Ching Lin / Fang R. Zhao / Hana Janova / Adrian Gervais / Summer Rucknagel / Kristy O. Murray / Jean-Laurent Casanova / Michael S. Diamond

Nature Communications, Vol 14, Iss 1, Pp 1-

2023  Band 16

Abstract: Abstract The determinants of severe disease caused by West Nile virus (WNV) and why only ~1% of individuals progress to encephalitis remain poorly understood. Here, we use human and mouse enteroids, and a mouse model of pathogenesis, to explore the ... ...

Abstract Abstract The determinants of severe disease caused by West Nile virus (WNV) and why only ~1% of individuals progress to encephalitis remain poorly understood. Here, we use human and mouse enteroids, and a mouse model of pathogenesis, to explore the capacity of WNV to directly infect gastrointestinal (GI) tract cells and contribute to disease severity. At baseline, WNV poorly infects human and mouse enteroid cultures and enterocytes in mice. However, when STAT1 or type I interferon (IFN) responses are absent, GI tract cells become infected, and this is associated with augmented GI tract and blood-brain barrier (BBB) permeability, accumulation of gut-derived molecules in the brain, and more severe WNV disease. The increased gut permeability requires TNF-α signaling, and is absent in WNV-infected IFN-deficient germ-free mice. To link these findings to human disease, we measured auto-antibodies against type I IFNs in serum from WNV-infected human cohorts. A greater frequency of auto- and neutralizing antibodies against IFN-α2 or IFN-ω is present in patients with severe WNV infection, whereas virtually no asymptomatic WNV-infected subjects have such antibodies (odds ratio 24 [95% confidence interval: 3.0 − 192.5; P = 0.003]). Overall, our experiments establish that blockade of type I IFN signaling extends WNV tropism to enterocytes, which correlates with increased gut and BBB permeability, and more severe disease.
Schlagwörter Science ; Q
Thema/Rubrik (Code) 616
Sprache Englisch
Erscheinungsdatum 2023-09-01T00:00:00Z
Verlag Nature Portfolio
Dokumenttyp Artikel ; Online
Datenquelle BASE - Bielefeld Academic Search Engine (Lebenswissenschaftliche Auswahl)

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