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.

The vaginal mycobiome: A contemporary perspective on fungi in women's health and diseases

“…48 It has also been shown that Lactobacillus indoleamine 2,3-dioxygenase 1 (IDO1) in the gut leads to the production of tryptophan catabolites that act on regulatory T cells, resulting in increased local expression of IL-22 49 and immunoprotection to VVC. 50 This suggests that the bacterial microbiome could be mediating tolerance to C. albicans on the mucosa.…”

CX 3 CR1 Is Dispensable for Control of Mucosal Candida albicans Infections in Mice and Humans

“…In agreement with the mouse data, the mutant human CX 3 CR1-M280 allele was shown to be an independent risk factor for the development of candidemia and disseminated candidiasis in two different cohorts of patients from the United States and Europe (10). However, whether this receptor plays a role in mucosal host defense against Candida is unknown.In recent years, it has become evident that interleukin 23 (IL-23)-dependent IL-17 and IL-22 signaling is critical for protection against mucosal candidiasis in mice and humans (11)(12)(13)(14)(15)(16)(17). Of interest, Cx3cr1 has previously been shown to promote IL-23-dependent IL-22 production and mucosal immune responses in the context of bacterial gastrointestinal (GI) tract infection and intestinal inflammation (18,19).…”

Experimental Models of Vaginal Candidiasis and Their Relevance to Human Candidiasis

“…Commensalismshaped immunity is likely to participate in specific mechanisms of C. albicans vaginal immune tolerance through a complex set of immune-regulatory responses. Among them, an experimentally supported concept is that tolerance is regulated by IL-22 and IDO (indoleamine 2,3-dioxygenase)-dependent tryptophan metabolism (kynurenins) (8). Importantly, tolerance can be overwhelmed or bypassed by a high burden of fungal cells, particularly in the hyphal forms, in the presence of the aforementioned typical factors predisposing subjects to candidal vaginitis.…”

“…With the above premise, the magnitude of the efforts made by a number of investigators to identify disease mechanisms and host inflammatory and immune responses in vaginal candidiasis by adopting animal models of the disease is admirable. In some cases, the data obtained by the use of the models described above directed the investigators toward the choice of vaccine candidates or, more recently, toward devising novel therapeutic options based on the control of pathogenic vaginal inflammation (4)(5)(6)(7)(8). Overall, research has now progressed to promising future important applications for effective disease control (4).…”