A fungal metabolic regulator underlies infectious synergism duringCandida albicans-Staphylococcusaureus intra-abdominal co-infection

Abstract

ABSTRACTCandida albicansandStaphylococcus aureusare two commonly associated pathogens that cause nosocomial infections with high morbidity and mortality. Our prior and current work using a murine model of polymicrobial intra-abdominal infection (IAI) uncovered synergistic lethality that was driven byCandida-induced upregulation of functionalS. aureus⍺-toxin leading to polymicrobial sepsis and organ damage. In order to determine the candidal effector(s) mediating enhanced virulence, an unbiased screen ofC. albicanstranscription factor mutants was undertaken and revealed thatzcf13Δ/Δ failed to drive augmented ⍺-toxin or lethal synergism during co-infection. Using a combination of transcriptional and phenotypic profiling approaches,ZCF13was shown to regulate genes involved in pentose metabolism, includingRBK1andHGT7that contribute to fungal ribose catabolism and uptake, respectively. Subsequent experiments revealed that ribose inhibited the staphylococcalagrquorum sensing system and concomitantly repressed toxicity. Unlike wild-typeC. albicans,zcf13Δ/Δ was unable to effectively utilize ribose during co-culture or co-infection leading to exogenous ribose accumulation andagrrepression. Forced expression ofRBK1andHGT7in thezcf13Δ/Δ mutant fully restored pathogenicity during co-infection. Collectively, our results detail the interwoven complexities of cross-kingdom interactions and highlight how intermicrobial metabolism impacts polymicrobial disease pathogenesis with devastating consequences for the host.