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Blockade of interferon signaling decreases gut barrier integrity and promotes severe West Nile virus disease

Author

Listed:
  • 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
    Imagine Institute)

  • 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
    Imagine Institute
    Rockefeller Branch, The Rockefeller University
    Howard Hughes Medical Institute)

  • Michael S. Diamond

    (Washington University School of Medicine
    Washington University School of Medicine
    Washington University School of Medicine
    Washington University School of Medicine)

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.

Suggested Citation

  • Shih-Ching Lin & Fang R. Zhao & Hana Janova & Adrian Gervais & Summer Rucknagel & Kristy O. Murray & Jean-Laurent Casanova & Michael S. Diamond, 2023. "Blockade of interferon signaling decreases gut barrier integrity and promotes severe West Nile virus disease," Nature Communications, Nature, vol. 14(1), pages 1-16, December.
  • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-41600-3
    DOI: 10.1038/s41467-023-41600-3
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