Cryptococcal Chitin Synthase 3 and Host Immune Responses

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PROJECT SUMMARY/ABSTRACT Cryptococcus neoformans infections are a significant cause of morbidity and mortality among AIDS patients and the third most common invasive fungal infection in organ transplant recipients. There are an estimated quarter million cases of cryptococcal meningitis each year resulting in ~200,000 deaths. Because host immune responses are so vital to the control of cryptococcosis, my long-term goal is to delineate the host: fungal interactions that impact C. neoformans pathogenesis or clearance. One of the main interfaces between the fungus and the host is the fungal cell wall. The cell wall in Cryptococcus is unusual in that the chitin is predominantly deacetylated to chitosan. Chitosan deficient strains of C. neoformans were found to be avirulent and were rapidly cleared from the murine lung. Moreover, infection with a chitosan deficient C. neoformans lacking three chitin deacetylases (cda1Δ2Δ3Δ) was found to confer protective immunity to a subsequent challenge with a virulent wild type counterpart. In addition to the chitin deacetylases, it was previously shown that chitin synthase 3 (Chs3) is also essential for chitin deacetylase mediated formation of chitosan. Mice inoculated with chs3Δ at a dose previously shown to induce protection with cda1Δ2Δ3Δ die within 36 hours after installation of the fungal organism. Death is dose dependent as mice given a lower dose did not succumb. Mortality was not dependent on viable fungi as mice inoculated with heat-killed chs3Δ died at the same rate as mice inoculated with live chs3Δ, suggesting that the rapid onset of death was host mediated likely caused by an over exuberant immune response. Altogether, these studies lead us to hypothesize that Chs3 plays a critical role in dampening cryptococcal induced host inflammatory responses. In this application we aim to define the mechanism(s) within the host that trigger the aberrant immune response to chs3Δ and identify the cellular component(s) from chs3Δ that elicit this non-protective pro-inflammatory response. The work proposed in this application will have significant overall impact on basic science knowledge, which will provide insights into other pathogenic microbes and areas of biology, as well as potentially advance our understanding of a significant problem in the management of cryptococcal patients. This K22 approach will provide me with opportunities to not only understand the pathways that drive the host response and the cryptococcal components that drive the immune response, but also the bifurcation between protective and non-protective innate host responses. The mentorship received in Drs. Wormley, Doering, and Lodge laboratories, as well as the knowledge and experiences gained has afforded me the skills and opportunities to become an independent researcher and to pursue a successful career studying host: pathogen interactions. This work will provide the foundation for future RO1 applications as well as a career investigating the host: fungal interactions that impact fungal pathogenesis or clearance.