Eosinophils subvert host resistance to an intracellular pathogen by instigating non-protective IL-4 in CCR2-/- mice

Mucosal Immunol. 2017 Jan;10(1):194-204. doi: 10.1038/mi.2016.26. Epub 2016 Apr 6.


Eosinophils contribute to type II immune responses in helminth infections and allergic diseases; however, their influence on intracellular pathogens is less clear. We previously reported that CCR2-/- mice exposed to the intracellular fungal pathogen Histoplasma capsulatum exhibit dampened immunity caused by an early exaggerated interleukin (IL)-4 response. We sought to identify the cellular source promulgating IL-4 in infected mutant animals. Eosinophils were the principal instigators of non-protective IL-4 and depleting this granulocyte population improved fungal clearance in CCR2-/- animals. The deleterious impact of eosinophilia on mycosis was also recapitulated in transgenic animals overexpressing eosinophils. Mechanistic examination of IL-4 induction revealed that phagocytosis of H. capsulatum via the pattern recognition receptor complement receptor (CR) 3 triggered the heightened IL-4 response in murine eosinophils. This phenomenon was conserved in human eosinophils; exposure of cells to the fungal pathogen elicited a robust IL-4 response. Thus, our findings elucidate a detrimental attribute of eosinophil biology in fungal infections that could potentially trigger a collapse in host defenses by instigating type II immunity.

MeSH terms

  • Animals
  • Antigens, Fungal / immunology
  • Cells, Cultured
  • Eosinophils / immunology*
  • Eosinophils / microbiology
  • Histoplasma / immunology*
  • Histoplasmosis / immunology*
  • Humans
  • Immune Evasion
  • Immunity, Innate
  • Interleukin-4 / metabolism*
  • Macrophage-1 Antigen / metabolism
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Phagocytosis
  • Receptors, CCR2 / genetics
  • Receptors, CCR2 / metabolism*


  • Antigens, Fungal
  • Ccr2 protein, mouse
  • Macrophage-1 Antigen
  • Receptors, CCR2
  • Interleukin-4