Candida albicans oscillating UME6 expression during intestinal colonization primes systemic Th17 protective immunity

Friendly fungi: symbiosis with commensal Candida albicans

“…These responses mimic those observed in SPF mice after 'rewilding', in which animals are released into an outdoor enclosure to acquire environmental microbes [58]. The use of recombinant C. albicans engineered to express defined model antigens to establish colonization in mice shows that fungal commensalism primes the accumulation of CD4 + T cells poised for production of the neutrophil-activating cytokine IL-17 [55,59].…”

“…Links between C. albicans dynamic gene expression and immunogenicity during intestinal colonization were recently investigated by varying the expression of UME6, a transcription factor responsible for promoting filamentation in response to environmental signals, since UME6-deficient (ume6 −/− ) C. albicans cells are defective for filamentation when grown under conditions (serum supplementation, 37°C, or nitrogen and carbon starvation) that promote filamentation in wildtype C. albicans [94][95][96]. The results showed that immunogenicity was lost in mice colonized by either UME6-deficient or UME6-overexpressing C. albicans, but restored in mice colonized by C. albicans forced to oscillate between UME6-on and UME6-off states, as evidenced by the relative accumulation of Th17 CD4 + T cells and the resistance of mice to wild-type C. albicans intravenous infection [59]. Moreover, β-glucan exposure, along with the expression of GSC1 and MNT2 required for β-glucan and mannan biosynthesis, respectively, were sharply reduced in both UME6-on and UME6-off locked states, with the levels of each rebounding in C. albicans fungi transitioning between the two states; this indicated that oscillating, instead of static, UME6 expression promoted the expression of these antigenic cell-wall components.…”

“…Here, donor B cells from SC5314-colonized mice overturned the susceptibility of B cell-deficient μMT −/− mice to a normally lethal intravenous dose of C. albicans and IgG from C. albicanscolonized mice also bypassed susceptibility caused by the myeloablative drug cyclophosphamide [52]. Additional studies highlighted the importance of Th17 cells, since administration of anti-CD4 cell depleting antibodies or anti-IL-17A and IL-17F cytokine neutralizing antibodies each overturned C. albicans colonization-induced protection against systemic infection, which persisted even in μMT −/− mice [55,59]. Of note, priming C. albicans-specific CD4 + T cells requires specialized antigen-presenting cells that express the autoimmune regulator (AIRE) transcriptional regulator, which may explain the increased susceptibility of individuals with autoimmune polyendocrine syndrome type 1 caused by spontaneous AIRE loss-of-function mutations [63,64].…”

“…Prior studies showed that C. albicans colonization in mice devoid of commensal bacteria (via multiple antibiotics) had increased survival compared with non-colonized control mice following dextran sulfate sodium (DSS)-induced colitis or infection by respiratory viral pathogens such as influenza A virus (IAV), indicating that commensal fungi can replace the tonic stimulatory effects of commensal bacteria [17]. More recent studies establishing colonization without antibiotics or using antibiotics with narrow scope to facilitate colonization [52,55,56] Th17 mediated, requires tonic stimulation [55] Antibody mediated [52] B cell independent [59] Protection against infection by other fungal pathogens…”

“…Teleologically, the accelerated replication of fungi (minutes to hours) compared with mammalian hosts (months to decades), should select for non-immunogenic commensals if immunogenicity has uniformly negative consequences for fungal fitness. Instead, fungal commensals actively stimulate immune cells via a variety of host PRRs, and the degree of C. albicans colonizationinduced protection against invasive infection is significantly reduced in mice with functional defects in TLR2, TLR4, Dectin-1, and Dectin-2 [59]. These antifungal receptors are expressed by multiple cell types including CX3CR1 mononuclear phagocyte cells, and conditional depletion of CX3CR1 in CD11c + antigen-presenting cells (diphtheria toxin administration to CD11c Cre CX3CR1 DTR mice) overrides the accumulation of IL-17-producing CD4 + T cells in the intestine of C. albicans-colonized mice [75].…”