Il4ra-independent vaginal eosinophil accumulation following helminth infection exacerbates epithelial ulcerative pathology of HSV-2 infection

Alisha Chetty, Matthew G Darby, Pia M Vornewald, Mara Martín-Alonso, Anna Filz, Manuel Ritter, Henry J McSorley, Lindi Masson, Katherine Smith, Frank Brombacher, Matthew K O'Shea, Adam F Cunningham, Bernhard Ryffel, Menno J Oudhoff, Benjamin G Dewals, Laura E Layland, William G C Horsnell

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Abstract

How helminths influence the pathogenesis of sexually transmitted viral infections is not comprehensively understood. Here, we show that an acute helminth infection (Nippostrongylus brasiliensis [Nb]) induced a type 2 immune profile in the female genital tract (FGT). This leads to heightened epithelial ulceration and pathology in subsequent herpes simplex virus (HSV)-2 infection. This was IL-5-dependent but IL-4 receptor alpha (Il4ra) independent, associated with increased FGT eosinophils, raised vaginal IL-33, and enhanced epithelial necrosis. Vaginal eosinophil accumulation was promoted by IL-33 induction following targeted vaginal epithelium damage from a papain challenge. Inhibition of IL-33 protected against Nb-exacerbated HSV-2 pathology. Eosinophil depletion reduced IL-33 release and HSV-2 ulceration in Nb-infected mice. These findings demonstrate that Nb-initiated FGT eosinophil recruitment promotes an eosinophil, IL-33, and IL-5 inflammatory circuit that enhances vaginal epithelial necrosis and pathology following HSV-2 infection. These findings identify a mechanistic framework as to how helminth infections can exacerbate viral-induced vaginal pathology.

Original languageEnglish
Pages (from-to)579-593.e5
JournalCell Host & Microbe
Volume29
Issue number4
Early online date12 Mar 2021
DOIs
Publication statusPublished - 14 Apr 2021

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