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Factors that determine these outcomes are not well-understood. In a mouse model of genital herpes simplex virus-2 (HSV-2) infection, which results in severe genital inflammation, antibody-mediated neutrophil depletion reduced disease. Comparative single-cell RNA-sequencing analysis of vaginal cells against a model of genital HSV-1 infection, which results in mild inflammation, demonstrated sustained expression of interferon-stimulated genes (ISGs) only after HSV-2 infection primarily within the neutrophil population. Both therapeutic blockade of IFN\u03b1\/\u03b2 receptor 1 (IFNAR1) and genetic deletion of IFNAR1 in neutrophils concomitantly decreased HSV-2 genital disease severity and vaginal IL-18 levels. Therapeutic neutralization of IL-18 also diminished genital inflammation, indicating an important role for this cytokine in promoting neutrophil-dependent immunopathology. Our study reveals that sustained type I interferon (IFN) signaling is a driver of pathogenic neutrophil responses and identifies IL-18 as a novel component of disease during genital HSV-2 infection.<\/jats:p>","DOI":"10.7554\/elife.65762","type":"journal-article","created":{"date-parts":[[2021,5,27]],"date-time":"2021-05-27T04:00:22Z","timestamp":1622088022000},"update-policy":"https:\/\/doi.org\/10.7554\/elife.65762","source":"Crossref","is-referenced-by-count":33,"title":["A sustained type I IFN-neutrophil-IL-18 axis drives pathology during mucosal viral infection"],"prefix":"10.7554","volume":"10","author":[{"given":"Tania","family":"Lebratti","sequence":"first","affiliation":[{"name":"Department of Medicine\/Division of Infectious Diseases, Washington University School of Medicine, St Louis, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ying Shiang","family":"Lim","sequence":"additional","affiliation":[{"name":"Department of Medicine\/Division of 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