A human commensal-pathogenic fungus suppresses host immunity via targeting TBK1.

Candida albicans stably colonizes humans but is the leading cause of hospital-acquired fungemia. Traditionally, masking immunogenic moieties has been viewed as a tactic for immune evasion. Here, we demonstrate that C. albicans blocks type I interferon (IFN-I) signaling via translocating an effector protein Cmi1 into host cells. Mechanistically, Cmi1 binds and inhibits TANK-binding kinase 1 (TBK1) to abrogate IFN-regulatory factor 3 (IRF3) phosphorylation, thereby suppressing the IFN-I cascade. Murine infection with a cmi1 mutant displays an exaggerated IFN-I response in both kidneys and bone-marrow-derived macrophages, leading to rapid fungal clearance and host survival. Remarkably, the lack of CMI1 compromises gut commensalism and increases IFN-I response in mouse colonic cells. These phenotypes of cmi1 are rescued by the depletion of IFN-I receptor. This work establishes the importance of TBK1 inhibition in fungal pathogenesis and reveals that a human commensal-pathogenic fungus significantly impacts host immunity during gut colonization and infection via delivering effector proteins into host cells. [Display omitted] • Candida albicans dampens type I IFN response in murine kidneys • C. albicans secretes an effector protein Cmi1 into host cytosol • Cmi1 binds TBK1 to abrogate IRF3 phosphorylation and IFN-I activation • Cmi1 targeting of TBK1 promotes virulence and gut colonization of C. albicans Luo et al. identify an effector protein Cmi1 in the human commensal-pathogenic fungus Candida albicans. Cmi1 targets TBK1 to abrogate type I interferon response. This work reveals that C. albicans significantly suppresses host immunity during gut colonization and infection, which could impact human health and disease other than causing infection. [ABSTRACT FROM AUTHOR]