title: Microbiota-Regulated IL-25 Increases Eosinophil Number to Provide Protection during Clostridium difficile Infection.
abstract: Clostridium difficile infection (CDI) is the most common cause of hospital-acquired infection in the United States. Host susceptibility and the severity of infection are influenced by disruption of the microbiota and the immune response. However, how the microbiota regulate immune responses to mediate CDI outcome remains unclear. Here, we have investigated the role of the microbiota-linked cytokine IL-25 during infection. Intestinal IL-25 was suppressed during CDI in humans and mice. Restoration of IL-25 reduced CDI-associated mortality and tissue pathology even though equivalent levels of C. difficile bacteria and toxin remained in the gut. IL-25 protection was mediated by gut eosinophils, as demonstrated by an increase in intestinal eosinophils and a loss of IL-25 protection upon eosinophil depletion. These findings support a mechanism whereby the induction of IL-25-mediated eosinophilia can reduce host mortality during active CDI. This work may provide targets for future development of microbial or immune-based therapies.
authors.affiliation: Department of Microbiology, Immunology and Cancer Biology, University of Virginia (UVA), Health Sciences Center, Charlottesville, VA 22908, USA.
authors.forename: Erica L
authors.initials: EL
authors.lastname: Buonomo
authors.affiliation: Department of Microbiology, Immunology and Cancer Biology, University of Virginia (UVA), Health Sciences Center, Charlottesville, VA 22908, USA.
authors.forename: Carrie A
authors.initials: CA
authors.lastname: Cowardin
authors.affiliation: Department of Microbiology, Immunology and Cancer Biology, University of Virginia (UVA), Health Sciences Center, Charlottesville, VA 22908, USA.
authors.forename: Madeline G
authors.initials: MG
authors.lastname: Wilson
authors.affiliation: Department of Microbiology, Immunology and Cancer Biology, University of Virginia (UVA), Health Sciences Center, Charlottesville, VA 22908, USA.
authors.forename: Mahmoud M
authors.initials: MM
authors.lastname: Saleh
authors.affiliation: Department of Pathology, University of Virginia (UVA), Health Sciences Center, Charlottesville, VA 22908, USA.
authors.forename: Patcharin
authors.initials: P
authors.lastname: Pramoonjago
authors.affiliation: Department of Microbiology, Immunology and Cancer Biology, University of Virginia (UVA), Health Sciences Center, Charlottesville, VA 22908, USA; Department of Medicine, University of Virginia (UVA), Health Sciences Center, Charlottesville, VA 22908, USA; Department of Pathology, University of Virginia (UVA), Health Sciences Center, Charlottesville, VA 22908, USA. Electronic address: wap3g@virginia.edu.
authors.forename: William A
authors.initials: WA
authors.lastname: Petri
mesh_terms: D000818:Animals; D016360:Clostridioides difficile / Q000276:immunology*; D004761:Enterocolitis, Pseudomembranous / Q000276:immunology / Q000378:metabolism* / Q000382:microbiology; D004804:Eosinophils / Q000276:immunology*; D005752:Gastric Mucins / Q000096:biosynthesis; D000069196:Gastrointestinal Microbiome; D006801:Humans; D015847:Interleukin-4 / Q000378:metabolism; D007378:Interleukins / Q000494:pharmacology / Q000502:physiology*; D007958:Leukocyte Count; D008297:Male; D008810:Mice, Inbred C57BL; D009092:Mucous Membrane / Q000276:immunology / Q000473:pathology; D065840:Protective Factors
chemical_list: D005752:Gastric Mucins; D007378:Interleukins; C442281:Mydgf protein, mouse; D015847:Interleukin-4