Candida albicans, the most commonly isolated human fungal pathogen, is responsible for a wide variety of systemic and mucosal infections. Immunocompromised individuals, including cancer patients on chemotherapy, AIDS patients, neonates, and organ transplant recipients, are particularly susceptible to infection. A central feature of C. albicans pathogenesis is this organism?s ability to counteract host immune defenses. In particular, C. albicans has evolved a variety of mechanisms to promote both survival in the phagosome of host macrophages as well as macrophage killing. While previous whole-genome transcriptional profiling experiments have provided important insights into these processes, very little is known about translational changes in gene expression that are associated with the C. albicans-macrophage interaction. Especially given that transcriptional analyses can often provide an imperfect proxy for monitoring protein expression due to extensive regulation of protein synthesis, studying translational control of the C. albicans-macrophage interaction is more likely to identify novel mechanisms required for C. albicans survival and pathogenicity as well as translational regulatory events associated with currently known mechanisms, that have not been previously characterized. Several lines of evidence suggest that translational mechanisms play an important role in the ability of C. albicans to survive in the phagosome and eventually kill host macrophages, including the observation that C. albicans proteins involved in a variety of processes critical for survival, including the glyoxylate cycle, fatty acid oxidation and the response to oxidative stress are expressed during the early stage of macrophage internalization, despite a widespread down-regulation of protein synthesis. Previous work from our laboratory has also shown that a key regulator of the C. albicans yeast-filament transition, important for macrophage lysis, is controlled by a 5? UTR-mediated translational efficiency mechanism and results from an RNA-seq analysis suggest that several C. albicans genes involved in processes important for macrophage survival and lysis could be controlled by a similar mechanism. Our hypothesis is that translational efficiency mechanisms play an important role in controlling C. albicans survival in the phagosome as well as macrophage killing. In order to address this hypothesis we will first, using whole- genome ribosome profiling, determine both host and pathogen global translational profiles associated with the C. albicans-macrophage interaction. Second, we will characterize selected translational mechanisms specifically important for C. albicans macrophage survival and killing. These studies will provide new and important information about how translational efficiency mechanisms promote the ability of a major human fungal pathogen to both survive in the phagosome and lyse host macrophages. Ultimately, common fungal- specific components of these mechanisms could serve as potential targets for the development of novel and more effective classes of antifungal therapies.
Relevance to public health: Candida albicans, a major human fungal pathogen responsible for life- threatening yeast infections in a wide variety of immunocompromised individuals, can both survive in and kill macrophages of the host immune system. This proposal seeks to determine how translational efficiency mechanisms control the C. albicans-macrophage interaction. Ultimately, this study will provide new information leading to the development of novel and more effective strategies to treat candidiasis.
