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 and Michael S. Diamond ()
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Shih-Ching Lin: Washington University School of Medicine
Fang R. Zhao: Washington University School of Medicine
Hana Janova: Washington University School of Medicine
Adrian Gervais: Necker Hospital for Sick Children
Summer Rucknagel: Washington University School of Medicine
Kristy O. Murray: Baylor College of Medicine and Texas Children’s Hospital
Jean-Laurent Casanova: Necker Hospital for Sick Children
Michael S. Diamond: Washington University School of Medicine

Nature Communications, 2023, vol. 14, issue 1, 1-16

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 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.

Date: 2023
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DOI: 10.1038/s41467-023-41600-3

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