title: Eosinophils subvert host resistance to an intracellular pathogen by instigating non-protective IL-4 in CCR2-/-mice.
abstract: 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.
authors.affiliation: Division of Immunobiology, Cincinnati Children's Hospital Medical Center, University of Cincinnati, Cincinnati, Ohio, USA.|Division of Infectious Diseases, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA.
authors.forename: A H
authors.initials: AH
authors.lastname: Verma
authors.affiliation: Division of Infectious Diseases, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA.
authors.forename: C L
authors.initials: CL
authors.lastname: Bueter
authors.affiliation: Division of Allergy and Immunology, Cincinnati Children's Hospital Medical Center, University of Cincinnati, Cincinnati, Ohio, USA.
authors.forename: M E
authors.initials: ME
authors.lastname: Rothenberg
authors.affiliation: Division of Infectious Diseases, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA.|Veterans Affairs Hospital, Cincinnati, Ohio, USA.
authors.forename: G S
authors.initials: GS
authors.lastname: Deepe
mesh_terms: D000818:Animals; D000946:Antigens, Fungal / Q000276:immunology; D002478:Cells, Cultured; D004804:Eosinophils / Q000276:immunology* / Q000382:microbiology; D006658:Histoplasma / Q000276:immunology*; D006660:Histoplasmosis / Q000276:immunology*; D006801:Humans; D057131:Immune Evasion; D007113:Immunity, Innate; D015847:Interleukin-4 / Q000378:metabolism*; D016177:Macrophage-1 Antigen / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010587:Phagocytosis; D054390:Receptors, CCR2 / Q000235:genetics / Q000378:metabolism*
chemical_list: D000946:Antigens, Fungal; C515335:Ccr2 protein, mouse; D016177:Macrophage-1 Antigen; D054390:Receptors, CCR2; D015847:Interleukin-4