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 (Lead / Corresponding author), William G. C. Horsnell (Lead / Corresponding author)

Research output: Contribution to journalArticlepeer-review

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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
Number of pages21
JournalCell Host & Microbe
Volume29
Issue number4
Early online date12 Mar 2021
DOIs
Publication statusPublished - 14 Apr 2021

Keywords

  • HSV-2
  • IL-33
  • IL-5
  • Nippostrongylus brasiliensis
  • eosinophils
  • epithelial ulceration
  • helminths
  • systemic immunity
  • vagina

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