IL-22 defines a novel immune pathway of antifungal resistance

Abstract

The role of IL-17 and Th17 cells in immunity vs. pathology associated with the human commensal Candida albicans remains controversial. Both positive and negative effects on immune resistance have been attributed to IL-17/Th17 in experimental candidiasis. In this study, we provide evidence that IL-22, which is also produced by Th17 cells, has a critical, first-line defense in candidiasis by controlling the growth of infecting yeasts as well as by contributing to the host's epithelial integrity in the absence of acquired Th1-type immunity. The two pathways are reciprocally regulated, and IL-22 is upregulated under Th1 deficiency conditions and vice versa. Whereas both IL-17A and F are dispensable for antifungal resistance, IL-22 mediates protection in IL-17RA-deficient mice, in which IL-17A contributes to disease susceptibility. Thus, our findings suggest that protective immunity to candidiasis is made up of a staged response involving an early, IL-22-dominated response followed by Th1/Treg reactivity that will prevent fungal dissemination and supply memory.

Sensing of mammalian IL-17A regulates fungal adaptation and virulence

“…In line with what is observed in humans 7 , Candida overgrowth occurs under conditions of defective interleukin (IL)-17F 8 or IL-17RA signalling [8][9][10] , which suggests the importance of IL-17RA signalling in preventing infection. Under specific circumstances, IL-17A may, in fact, contribute to disease susceptibility in a host-autonomous fashion, perhaps by modifying the intrinsic virulence of the fungus 8 . In this study, we provide molecular evidence that fungal pathogens may exploit, via a conserved family of glycosylphosphatidylinositol (GPI)-anchored crosslinking proteins, host immunity mediatorsspecifically, IL-17A-for adaptation, not necessarily implicating virulence, and pathogenesis in mammalian hosts.…”

Characterization of IL-22 and antimicrobial peptide production in mice protected against pulmonary Cryptococcus neoformans infection

“…In studies of Candida albicans vaginitis, the S100 antimicrobial peptides have been examined, and data have shown that their role is more important in neutrophil recruitment than in direct microbicidal activity against Candida (Johnston et al, 2013;Yano et al, 2010Yano et al, , 2012a. However, additional studies by other laboratories have shown that IL-22 is critical to protection in a vaginal model of Candida albicans infection (De Luca et al, 2010. Furthermore, our in vitro studies did not show anti-fungal activity of any of the purified AMPs against C. neoformans (data not shown).…”

RORγt+ innate lymphoid cells regulate intestinal homeostasis by integrating negative signals from the symbiotic microbiota

“…After birth, the key role of IL-22 in intestinal homeostasis and defense, and more generally in mucosal immunity, is well documented 10,12,13 . It may therefore not come as a surprise that the immune system has evolved a constitutive pathway for the production of IL-22.…”

“…We now show that RORγt + ILCs produce most of intestinal IL-22 at steady state and markedly increase this activity during inflammation. RORγt + ILCs therefore play a critical role in intestinal homeostasis and defense, as IL-22 induces the production of anti-bacterial peptides by epithelial cells, is required for intestinal defense against bacterial and fungal pathogens [8][9][10]12,13 and is involved in protection of intestinal tissues from the effects of pathological inflammation, presumably through the induction of anti-apoptotic factors 15, 16 .…”

“…Another member of the IL-10 cytokine family, IL-22, has been shown to directly induce epithelial defense through the expression of anti-microbial peptides, such as β-defensins 8 , S100A7 (psoriasin), S100A8 (calgranulin A), S100A9 (calgranulin B) 9 , RegIIIβ and RegIIIγ 10 . IL-22 plays a critical role in defense against attaching and effacing bacterial pathogens in the intestine, such as Citrobacter rodentium 10,11 , Gram-negative bacteria in the lung, such as Klebsiella pneumoniae 12 and against the fungi Candida albicans 13 . IL-22 also induces anti-apoptotic molecules, such as Bcl-2 family members, through the activation of STAT3 (ref.…”