Summary: Candida albicans infection is the third most common infection in hospitalized patients, with a mortality rate ranging between 14.5%?49%. Disseminated candidiasis causes kidney failure resulting in severe morbidity of the immunocompromised host such as those with acquired immune deficiency syndrome or cancer, organ or bone marrow transplant patients, or patients taking immunosuppressant drugs an extended period of time. Prevention and treatment of disseminated candidiasis are an important clinical problem, and currently, there are no approved vaccines against any fungal pathogens. However, the cellular and molecular mechanisms underlying renal failure caused by pathogenic Candida albicans infection remain largely unknown. The immune system plays an important role in protecting against disseminated candidiasis. Immune activating pathways in renal antigen-presenting cells (APCs) play a critical role in inducing robust immune responses in the kidney against C. albicans. In contrast, the anti-inflammatory pathways in APCs suppress immune responses in the kidney against C. albicans and increasing susceptibility to kidney damage and failure. Thus, identifying the signaling pathways that program APCs towards an immunogenic state versus a regulatory state will help identify new targets for therapeutic manipulation of immune cells that augments kidney immunity against Candida albicans and protects against infection-associated-kidney damage and failure. We have identified a new and previously unsuspected role for ?-catenin and TCF4 as a key molecular anti-inflammatory pathway in APCs that is critical for suppressing immune responses against disseminated candidiasis, causing increased susceptibility to kidney damage and failure. This application aims to delineate the molecular mechanisms by which ?-catenin and TCF4 metabolically program renal APCs against disseminated candidiasis and its impact on kidney function.
- National Institute of Allergy and Infectious Diseases: $231,000.00
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