Microbiota-driven interleukin-17 production provides immune protection against invasive candidiasis

Abstract

Background: The intestinal microbiota plays a crucial role in human health, which could affect host immunity and the susceptibility to infectious diseases. However, the role of intestinal microbiota in the immunopathology of invasive candidiasis remains unknown. Methods: In this work, an antibiotic cocktail was used to eliminate the intestinal microbiota of conventionalhoused (CNV) C57/BL6 mice, and then both antibiotic-treated (ABX) mice and CNV mice were intravenously infected with Candida albicans to investigate their differential responses to infection. Furthermore, fecal microbiota transplantation (FMT) was applied to ABX mice in order to assess its effects on host immunity against invasive candidiasis after restoring the intestinal microbiota, and 16S ribosomal RNA gene sequencing was conducted on fecal samples from both uninfected ABX and CNV group of mice to analyze their microbiomes. Results: We found that ABX mice displayed significantly increased weight loss, mortality, and organ damage during invasive candidiasis when compared with CNV mice, which could be alleviated by FMT. In addition, the level of IL-17A in ABX mice was significantly lower than that in the CNV group during invasive candidiasis. Treatment with recombinant IL-17A could improve the survival of ABX mice during invasive candidiasis. Besides, the microbial diversity of ABX mice was significantly reduced, and the intestinal microbiota structure of ABX mice was significantly deviated from the CNV mice. Conclusions: Our data revealed that intestinal microbiota plays a protective role in invasive candidiasis by enhancing IL-17A production in our model system.

Fabrication of levofloxacin-loaded porcine acellular dermal matrix hydrogel and functional assessment in urinary tract infection

“…Previous studies have consistently indicated that the administration of levofloxacin can disturb the equilibrium of the intestinal microbiota, thereby inducing antibiotic-associated inflammation within the gastrointestinal tract [55]. Moreover, previous research conducted by our team and other scholars has provided evidence that the depletion of the intestinal microbiota resulting from the administration of antimicrobial drugs substantially elevates the likelihood of bacterial infectious diseases [53,54,[72][73][74]. This correlation is closely linked to the reduction of immunoregulatory metabolites derived from the intestinal microbiota.…”

Long-distance relationships - regulation of systemic host defense against infections by the gut microbiota

“…Many of the microbiota-immune connections noted above were discovered, in part, through the demonstration that these mechanisms of systemic host defense fail when the microbiota is disrupted by antibiotics or absent in GF mice [16][17][18][19][20][21][22][23][24] . Intestinal dysbiosis in both animals and humans has been linked to increased susceptibility to bacterial, viral, and fungal pathogens 20,21,[114][115][116][117] . However, failure of microbiota-dependent host defense mechanisms is not the only consequence of intestinal dysbiosis during infection, as it is now appreciated that dysbiosis can also actively induce pathological systemic inflammation and immune-mediated organ damage in response to infection (ie.…”

Progranulin aggravates lethal Candida albicans sepsis by regulating inflammatory response and antifungal immunity

“…A systemic candidiasis mouse model was established according to previous studies [20,21], in which the kidney was the primary target organ, and mice developed renal failure and sepsis, and this recapitulated the progressive sepsis seen in humans during severe clinical cases. Firstly, we found that PGRN levels in the kidney, lung, liver, spleen, brain and blood were substantially increased at day 1 and lasted to day 9 after invasive C. albicans infection (Fig 1A).…”

“…immune reactions were an important cause of tissue damage and death in the murine Candida infection model [19][20][21][22]. Despite that PGRN KO mice had similar fungal burden in the kidney, which is the primary infected organ in the systemic candidiasis mouse model, at the early times of C. albicans infection (days 1, 4, and 7), the production of proinflammatory cytokine IL-6, a major cause of sepsis [37,38], in PGRN-deficient mice was significantly lower than that in WT animals.…”

“…Thus, the early decrease in inflammatory mediator production and macrophage/neutrophil recruitment observed in PGRN-deficient mice might contribute to the improvement in renal function and survival after C. albicans infection. On the other hand, PGRN-deficient mice displayed significantly higher production of INF-γ, IL-17A and IL-23 at early times after C. albicans infection, and these cytokines have been identified as protective factors against IC [21,23,40,41]. In fact, PGRN has been shown to be able to inhibit Th1 and Th17 cells, and significantly lower levels of INF-γ and IL-17 were observed in PGRNdeficient mice compared with WT mice in experimental autoimmune encephalomyelitis, experimental autoimmune uveitis or coxsackievirus-B3-induced viral myocarditis [42][43][44].…”