Enteric helminth coinfection enhances host susceptibility to neurotropic flaviviruses via a tuft cell-IL-4 receptor signaling axis

Pritesh Desai, Hana Janova, James P. White, Glennys V. Reynoso, Heather D. Hickman, Megan T. Baldridge, Joseph F. Urban, Thaddeus S. Stappenbeck, Larissa B. Thackray, Michael S. Diamond

Research output: Contribution to journalArticlepeer-review

9 Scopus citations

Abstract

Although enteric helminth infections modulate immunity to mucosal pathogens, their effects on systemic microbes remain less established. Here, we observe increased mortality in mice coinfected with the enteric helminth Heligmosomoides polygyrus bakeri (Hpb) and West Nile virus (WNV). This enhanced susceptibility is associated with altered gut morphology and transit, translocation of commensal bacteria, impaired WNV-specific T cell responses, and increased virus infection in the gastrointestinal tract and central nervous system. These outcomes were due to type 2 immune skewing, because coinfection in Stat6−/− mice rescues mortality, treatment of helminth-free WNV-infected mice with interleukin (IL)-4 mirrors coinfection, and IL-4 receptor signaling in intestinal epithelial cells mediates the susceptibility phenotypes. Moreover, tuft cell-deficient mice show improved outcomes with coinfection, whereas treatment of helminth-free mice with tuft cell-derived cytokine IL-25 or ligand succinate worsens WNV disease. Thus, helminth activation of tuft cell-IL-4-receptor circuits in the gut exacerbates infection and disease of a neurotropic flavivirus. Desai et al. show that the tuft cell/IL-4Rα circuit in the intestine can have detrimental consequences in the context of helminth and viral coinfection. Flavivirus infection of enteric neurons, in the setting of a type 2 immune response due to helminths, IL-25, or IL-4 signaling, impairs intestinal integrity and compromises host CD8+ T cell responses and survival.

Original languageEnglish
Pages (from-to)1214-1231.e16
JournalCell
Volume184
Issue number5
DOIs
StatePublished - Mar 4 2021

Keywords

  • CD8+ T cells
  • IL-4
  • flavivirus
  • helminth
  • microbiome
  • succinate
  • tuft cells
  • type 2 immunity
  • viral pathogenesis

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