Candida aurisevades innate immunity by using metabolic strategies to escape and kill macrophages while avoiding antimicrobial inflammation

Abstract

ABSTRACTCandida auriscauses life-threatening, drug-resistant infections. In addition to drug resistance, therapeutic innovation is hindered by our limited knowledge of the mechanisms used byC. auristo evade immunity and establish infection. Here we show thatC. aurisescapes phagocytic containment and kills macrophages, and demonstrate that the mechanisms rely on metabolic regulation. We found thatC. auris-infected macrophages undergo immunometabolic reprogramming and increase glycolysis but this does not lead to the expected antimicrobial responses, as macrophages fail to activate IL-1β cytokine and curbC. aurisgrowth. Further analysis showed thatC. aurisrelies on its own metabolic capacity to egress from macrophages, cause macrophage metabolic stress and cell death, and establish infectionin vivo. We identified a transcriptional regulator ofC. aurismetabolism and macrophage evasion, and further show that, contrary to several other pathogens,C. auris-induced macrophage metabolic dysfunction and death fail to activate the NLRP3 inflammasome. Consequently, inflammasome-dependent antimicrobial responses remain inhibited throughout infection. Our findings establish a pivotal role for metabolic regulation in enablingC. auristo eliminate macrophages while remaining immunologically silent to ensure its own survival.