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

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

doi:10.1371/journal.ppat.1003486

Antonella De Luca, Gloria Giovannini + Show 13 more

Open Access

https://doi.org/10.1371/journal.ppat.1003486

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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.

Highlights

Candida species are the causative agents of vulvovaginal candidiasis (VVC) and recurrent VVC (RVVC), two forms of disease that affect a large number of otherwise healthy women [1,2]
This study demonstrates that IL-22 and IDO1 mediate antifungal resistance and tolerance to C. albicans in the vagina and that their deficiencies are risk factors for RVVC
Wild-type and IL-22-deficient, but not IDO1-deficient mice, showed resistance to re-infection (Figure S1A in Text S1), a memory response requiring an intact T cell compartment (Figure S1B–E in Text S1). These findings suggest that IL-22 mediates early antifungal resistance, whereas IDO1 is required to restrain inflammation during ongoing infection and to provide antifungal memory

Summary

Introduction

Candida species are the causative agents of vulvovaginal candidiasis (VVC) and recurrent VVC (RVVC), two forms of disease that affect a large number of otherwise healthy women [1,2]. Despite a growing list of recognized risk factors, further understanding of anti-Candida host defense mechanisms in the vagina is needed to optimize vaccine development [3,4] and immune interventions to integrate with, or even replace, antifungal therapy. As IL-22 is known to contribute to antifungal resistance at mucosal surfaces by assuring epithelial integrity [13,14,15], and low levels of IL-22 are associated with chronic and recurrent mucosal candidiasis [16,17,18,19], a role for this cytokine in vaginal immune resistance, beyond the polymorphonuclear neutrophil’s (PMNs) response and alarmins production [20], is likely

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