title: IL-22 and IDO1 affect immunity and tolerance to murine and human vaginal candidiasis.
abstract: The ability to tolerate Candida albicans, a human commensal of the gastrointestinal tract and vagina, implicates that host defense mechanisms of resistance and tolerance cooperate to limit fungal burden and inflammation at the different body sites. We evaluated resistance and tolerance to the fungus in experimental and human vulvovaginal candidiasis (VVC) as well as in recurrent VVC (RVVC). Resistance and tolerance mechanisms were both activated in murine VVC, involving IL-22 and IL-10-producing regulatory T cells, respectively, with a major contribution by the enzyme indoleamine 2,3-dioxygenase 1 (IDO1). IDO1 was responsible for the production of tolerogenic kynurenines, such that replacement therapy with kynurenines restored immunoprotection to VVC. In humans, two functional genetic variants in IL22 and IDO1 genes were found to be associated with heightened resistance to RVVC, and they correlated with increased local expression of IL-22, IDO1 and kynurenines. Thus, IL-22 and IDO1 are crucial in balancing resistance with tolerance to Candida, their deficiencies are risk factors for RVVC, and targeting tolerance via therapeutic kynurenines may benefit patients with RVVC.
authors.affiliation: Department of Experimental Medicine and Biochemical Sciences, University of Perugia, Perugia, Italy.
authors.forename: Antonella
authors.initials: A
authors.lastname: De Luca
authors.forename: Agostinho
authors.initials: A
authors.lastname: Carvalho
authors.forename: Cristina
authors.initials: C
authors.lastname: Cunha
authors.forename: Rossana G
authors.initials: RG
authors.lastname: Iannitti
authors.forename: Lucia
authors.initials: L
authors.lastname: Pitzurra
authors.forename: Gloria
authors.initials: G
authors.lastname: Giovannini
authors.forename: Antonella
authors.initials: A
authors.lastname: Mencacci
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Bartolommei
authors.forename: Silvia
authors.initials: S
authors.lastname: Moretti
authors.forename: Cristina
authors.initials: C
authors.lastname: Massi-Benedetti
authors.forename: Dietmar
authors.initials: D
authors.lastname: Fuchs
authors.forename: Flavia
authors.initials: F
authors.lastname: De Bernardis
authors.forename: Paolo
authors.initials: P
authors.lastname: Puccetti
authors.forename: Luigina
authors.initials: L
authors.lastname: Romani
mesh_terms: D000818:Animals; D002176:Candida albicans / Q000187:drug effects / Q000276:immunology* / Q000302:isolation & purification; D002181:Candidiasis, Vulvovaginal / Q000235:genetics / Q000276:immunology* / Q000378:metabolism / Q000382:microbiology; D005260:Female; D056726:Genetic Association Studies; D014644:Genetic Variation; D006801:Humans; D007108:Immune Tolerance / Q000187:drug effects; D018928:Immunity, Mucosal / Q000187:drug effects; D007155:Immunologic Factors / Q000378:metabolism / Q000627:therapeutic use; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000235:genetics / Q000378:metabolism*; D016753:Interleukin-10 / Q000096:biosynthesis; D007378:Interleukins / Q000096:biosynthesis* / Q000235:genetics; D007737:Kynurenine / Q000378:metabolism / Q000627:therapeutic use; D051379:Mice; D008810:Mice, Inbred C57BL; D016513:Mice, SCID; D012008:Recurrence; D016511:Severe Combined Immunodeficiency / Q000188:drug therapy / Q000276:immunology / Q000503:physiopathology; D013047:Specific Pathogen-Free Organisms; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D000097043:Interleukin-22
chemical_list: D007155:Immunologic Factors; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D016753:Interleukin-10; D007378:Interleukins; D007737:Kynurenine; D000097043:Interleukin-22; C576710:IDO1 protein, human; C583637:IDO1 protein, mouse; C556062:IL10 protein, mouse