Pathogen and immune-topographic mechanisms that underpin Candida auris skin colonization - Project Summary/Abstract: Candida auris is an emerging drug-resistant fungal pathogen that is now endemic to all inhabited continents. C. auris colonizes human skin with extraordinary tenacity, and skin colonization is key to both its high rate of person- to-person transmission and the progression to infectious disease. There are currently no effective strategies to reverse colonization, and very little is known about how C. auris interacts with the structural and immune components of skin. Here we will leverage our team’s strengths across fungal pathogenesis and tissue immunology to address the mechanism of C. auris skin colonization. In preliminary work, we developed mouse models of C. auris skin colonization and rechallenge. We have begun to characterize C. auris behaviors on skin, the host immune response, and have performed a screen for fungal mediators of skin association. Our major findings include: 1) diverse clinical C. auris isolates exhibit enhanced skin colonization activity in mouse models relative to Candida albicans, a second fungal pathobiont commonly found on human skin; 2) C. auris but not C. albicans directly binds to hair and colonizes hair follicles in animals; 3) host immune responses to C. albicans and C. auris are starkly different, with IL-17-driven type 3 immunity predominating in C. albicans, and IFNγ- driven type 1 immunity predominating in C. auris; 4) IL-17 plays a far more modest role in restricting C. auris skin colonization as compared with C. albicans, whereas IFNγ surprisingly enhances colonization by C. auris but not C. albicans. We hypothesize that C. auris possesses unique virulence mechanisms that allow it to preferentially colonize and survive in hair follicles, from where it drives a protective IFN-associated type 1 immune response. Here, we propose to build on these observations to discover the mechanisms underlying C. auris’s enhanced capacity for skin colonization, as well as the role of IFN𝛄𝛄 and IL-17A cellular sources and targets, with potentially crucial implications for infection control and a broader understanding of how immune topography can impact skin health and disease. The specific goals of this proposal are to (1) identify C. auris factors required for hair binding and skin colonization, (2) decipher how type 1 lymphocytes and IFNγ signaling support C. auris skin colonization, and (3) define how fungal effectors and skin immune pathways intersect.
