Gastrointestinal colonization by Candida albicans modulates host defence in sepsis

Abstract

Pathological dysbiosis of the intestinal microbiome can lead to defects in immune homeostasis and a breakdown in host defense that increases susceptibility to infection. This is particularly relevant in patients with sepsis, a disorder of infection-induced systemic immune dysregulation and multi-organ dysfunction, where dysbiosis of the bacterial microbiome in these patients has been associated with adverse clinical outcomes. However, the impact of the fungal microbiome on sepsis pathogenesis has not been characterized. Analysis of the gut fungal microbiome in critically ill patients with sepsis identified severe fungal dysbiosis driven by marked overgrowth of Candida. Based on these clinical observations, we sought to investigate the functional impact of intestinal Candida overgrowth on systemic inflammation and host defense using mouse models. We colonized the gastrointestinal tracts of antibiotic-conditioned SPF C57BL/6 mice with different strains of C. albicans (including hyphal and yeast morphotypes) for 10 days prior to infection/sepsis with a well-characterized model of S. aureus bloodstream infection. The data indicated that colonizing mice with a yeast-locked strain of C. albicans displayed reduced illness severity, reduced systemic inflammation, and enhanced protection against systemic pathogen dissemination compared to uncolonized mice. In contrast, mice colonized with hyphal/filamentous C. albicans displayed similar illness severity, systemic inflammation, and pathogen burden as uncolonized controls. Further analysis of the immune landscape with mass cytometry indicated that yeast colonized mice have increased liver neutrophils. To test the therapeutic applicability of these findings, we treated hyphal colonized with yeast C. albicans to determine if it could displace hyphal C. albicans and impart immunological benefits. We found that yeast-treated mice had hyphal C. albicans physically displaced from their gut compartment by yeast treatment, and these treated mice had reductions in systemic pathogen burden. To expand upon this, we determined that genetically yeast locked strains (flo8-/-) are also able to displace wild-type C. albicans (SC5314), suggesting that these findings are likely applicable to a diverse amount of yeast-locked strains. Together, this project determined the impact of C. albicans gut colonization on the systemic host response, while describing immune mechanisms mediating this response and identifying the therapeutic potential of treatment with yeast C. albicans.