IL-22 and IDO1 affect immunity and tolerance to murine and human vaginal candidiasis

Antonella De Luca; Agostinho Carvalho; Cristina Cunha; Rossana G Iannitti; Lucia Pitzurra; Gloria Giovannini; Antonella Mencacci; Lorenzo Bartolommei; Silvia Moretti; Cristina Massi-Benedetti; Dietmar Fuchs; Flavia De Bernardis; Paolo Puccetti; Luigina Romani

doi:10.1371/journal.ppat.1003486

IL-22 and IDO1 affect immunity and tolerance to murine and human vaginal candidiasis

PLoS Pathog. 2013;9(7):e1003486. doi: 10.1371/journal.ppat.1003486. Epub 2013 Jul 11.

Authors

Antonella De Luca¹, Agostinho Carvalho, Cristina Cunha, Rossana G Iannitti, Lucia Pitzurra, Gloria Giovannini, Antonella Mencacci, Lorenzo Bartolommei, Silvia Moretti, Cristina Massi-Benedetti, Dietmar Fuchs, Flavia De Bernardis, Paolo Puccetti, Luigina Romani

Affiliation

¹ Department of Experimental Medicine and Biochemical Sciences, University of Perugia, Perugia, Italy.

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Candida albicans / drug effects
Candida albicans / immunology*
Candida albicans / isolation & purification
Candidiasis, Vulvovaginal / genetics
Candidiasis, Vulvovaginal / immunology*
Candidiasis, Vulvovaginal / metabolism
Candidiasis, Vulvovaginal / microbiology
Female
Genetic Association Studies
Genetic Variation
Humans
Immune Tolerance* / drug effects
Immunity, Mucosal* / drug effects
Immunologic Factors / metabolism
Immunologic Factors / therapeutic use
Indoleamine-Pyrrole 2,3,-Dioxygenase / genetics
Indoleamine-Pyrrole 2,3,-Dioxygenase / metabolism*
Interleukin-10 / biosynthesis
Interleukin-22
Interleukins / biosynthesis*
Interleukins / genetics
Kynurenine / metabolism
Kynurenine / therapeutic use
Mice
Mice, Inbred C57BL
Mice, SCID
Recurrence
Severe Combined Immunodeficiency / drug therapy
Severe Combined Immunodeficiency / immunology
Severe Combined Immunodeficiency / physiopathology
Specific Pathogen-Free Organisms
T-Lymphocytes, Regulatory / drug effects
T-Lymphocytes, Regulatory / immunology*
T-Lymphocytes, Regulatory / metabolism

Substances

IDO1 protein, human
IDO1 protein, mouse
IL10 protein, mouse
Immunologic Factors
Indoleamine-Pyrrole 2,3,-Dioxygenase
Interleukins
Interleukin-10
Kynurenine

Grants and funding

This study was supported by the Specific Targeted Research Project “ALLFUN” (FP7–HEALTH–2009 Contract number 260338 to LR). AC and CC were financially supported by fellowships from Fundação para a Ciência e Tecnologia, Portugal (contracts SFRH/BPD/46292/2008 and SFRH/BD/65962/2009, respectively). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.