title: IL-17A promotes protective IgA responses and expression of other potential effectors against the lumen-dwelling enteric parasite Giardia.
abstract: Giardia lamblia is a leading protozoan cause of diarrheal disease worldwide. It colonizes the lumen and epithelial surface of the small intestine, but does not invade the mucosa. Acute infection causes only minimal mucosal inflammation. Effective immune defenses exist, yet their identity and mechanisms remain incompletely understood. Interleukin (IL)-17A has emerged as an important cytokine involved in inflammation and antimicrobial defense against bacterial pathogens at mucosal surfaces. In this study, we demonstrate that IL-17A has a crucial function in host defense against Giardia infection. Using murine infection models with G. muris and G. lamblia, we observed marked and selective induction of intestinal IL-17A with peak expression after 2 weeks. Th17 cells in the lamina propria and innate immune cells in the epithelial compartment of the small intestine were responsible for the IL-17A response. Experiments in gene-targeted mice revealed that the cytokine, and its cognate receptor IL-17RA, were required for eradication of the parasite. The actions of the cytokine were mediated by hematopoietic cells, and were required for the transport of IgA into the intestinal lumen, since IL-17A deficiency led to marked reduction of fecal IgA levels, as well as for increased intestinal expression of several other potential effectors, including β-defensin 1 and resistin-like molecule β. In contrast, intestinal hypermotility, another major antigiardial defense mechanism, was not impacted by IL-17A loss. Taken together, these findings demonstrate that IL-17A and IL-17 receptor signaling are essential for intestinal defense against the important lumen-dwelling intestinal parasite Giardia.
authors.affiliation: Department of Internal Medicine, University of Texas Medical Branch, Galveston, TX, USA; Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX, USA.
authors.forename: Sara M
authors.initials: SM
authors.lastname: Dann
authors.affiliation: Department of Medicine, University of California, San Diego, CA, USA.
authors.forename: Carolin F
authors.initials: CF
authors.lastname: Manthey
authors.affiliation: Department of Medicine, University of California, San Diego, CA, USA.
authors.forename: Christine
authors.initials: C
authors.lastname: Le
authors.affiliation: Department of Medicine, University of California, San Diego, CA, USA.
authors.forename: Yukiko
authors.initials: Y
authors.lastname: Miyamoto
authors.affiliation: Department of Medicine, University of California, San Diego, CA, USA.
authors.forename: Lauren
authors.initials: L
authors.lastname: Gima
authors.affiliation: Department of Internal Medicine, University of Texas Medical Branch, Galveston, TX, USA.
authors.forename: Andrew
authors.initials: A
authors.lastname: Abrahim
authors.affiliation: Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX, USA.
authors.forename: Anthony T
authors.initials: AT
authors.lastname: Cao
authors.affiliation: Department of Medicine, University of California, San Diego, CA, USA.
authors.forename: Elaine M
authors.initials: EM
authors.lastname: Hanson
authors.affiliation: Department of Pediatrics, University of Pittsburgh, Pittsburgh, PA, USA.
authors.forename: Jay K
authors.initials: JK
authors.lastname: Kolls
authors.affiliation: Department of Medicine, University of California, San Diego, CA, USA.
authors.forename: Eyal
authors.initials: E
authors.lastname: Raz
authors.affiliation: Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX, USA; Department of Pathology, University of Texas Medical Branch, Galveston, TX, USA.
authors.forename: Yingzi
authors.initials: Y
authors.lastname: Cong
authors.affiliation: Department of Medicine, University of California, San Diego, CA, USA. Electronic address: leckmann@ucsd.edu.
authors.forename: Lars
authors.initials: L
authors.lastname: Eckmann
mesh_terms: D000818:Animals; D000913:Antibodies, Protozoan / Q000096:biosynthesis* / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D002678:Chimera; D005872:Giardia / Q000276:immunology*; D016829:Giardia lamblia / Q000276:immunology; D005873:Giardiasis / Q000276:immunology*; D006412:Hematopoietic Stem Cells / Q000276:immunology; D007070:Immunoglobulin A / Q000096:biosynthesis* / Q000276:immunology; D020381:Interleukin-17 / Q000235:genetics / Q000378:metabolism*; D007413:Intestinal Mucosa / Q000276:immunology / Q000469:parasitology; D007421:Intestine, Small / Q000276:immunology / Q000469:parasitology; D051379:Mice; D008810:Mice, Inbred C57BL; D012333:RNA, Messenger / Q000378:metabolism; D015398:Signal Transduction / Q000276:immunology; D013047:Specific Pathogen-Free Organisms; D058504:Th17 Cells / Q000276:immunology
chemical_list: D000913:Antibodies, Protozoan; D007070:Immunoglobulin A; D020381:Interleukin-17; D012333:RNA, Messenger
keywords: Cytokines; Mucosal immunity; Protozoan parasites; Small intestine