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

Cell. 2021 Mar 4;184(5):1214-1231.e16. doi: 10.1016/j.cell.2021.01.051. Epub 2021 Feb 25.


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.

Keywords: CD8+ T cells; IL-4; flavivirus; helminth; microbiome; succinate; tuft cells; type 2 immunity; viral pathogenesis.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • CD8-Positive T-Lymphocytes / immunology
  • Coinfection*
  • Disease Models, Animal
  • Disease Susceptibility
  • Intestinal Mucosa / parasitology
  • Intestinal Mucosa / virology
  • Mice
  • Mice, Inbred C57BL
  • Nematospiroides dubius / physiology*
  • Neurons / parasitology
  • Neurons / virology
  • Receptors, Interleukin-4 / metabolism
  • STAT6 Transcription Factor / genetics
  • Severity of Illness Index
  • Signal Transduction*
  • Strongylida Infections / parasitology
  • Strongylida Infections / pathology*
  • West Nile virus / physiology*


  • Receptors, Interleukin-4
  • STAT6 Transcription Factor
  • Stat6 protein, mouse