Innate immune mechanisms of the host response to Coccidioides

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Summary – Project 1 Project 1 is a new collaborative approach to understand the innate immune pathways involved in the host response to Coccidioides, an invasive pathogenic fungus resulting in 20,000 infections in the US annually. Only 1-2% of patients infected develop a severe and frequently lethal form, known as disseminated coccidiomycosis which affects brain, bones, and/or skin and usually requires lifelong therapy with anti-fungal drugs to prevent death and reduce morbidity. The factors determining the course of infected patients are not known, but it is likely that there is innate immune dysregulation in many of these patients that is genetically determined. While we have learned a great deal about the normal host response to common invasive fungal pathogens such as Candida and Aspergillus, there still remains much to be learned about Coccidioides. We will utilize a multi-pronged approach focusing on each major step of the innate immune response including 1) pattern recognition 2) cytokine responses and 3) pathogen processing, and on the specific molecular levels of this response such as RNA transcriptional regulation and cross-talk, protein translation and post-translation processing, as well as cell function and cell-cell interaction. To accomplish our goals, we have built a coalition of biomedical investigators at UCSD with a long history of collaboration, but a relatively new shared interest in Coccidioides and an expert with more than 40 years of experience studying Coccidioides. Aim 1. Define the mechanisms by which Dectin-1 and inhibitory Siglecs regulate human myeloid cell responses to coccidioides. Using myeloid cells from normal human donors we will characterize how human dectin-1 recognition of Coccidioides regulates gene expression programs. Using gain-of-function studies we will determine how iSiglec engagement inhibits Dectin-1 signaling. Finally, we will determine how human polymorphisms in Dectin-1 signaling pathways alter the cellular immune response to Coccidioides. Aim 2. Identify the cellular source of IL-1 and IL-1 in coccidioides infection and the inflammasome dependent and independent pathways controlling their processing and release Using human blood cells from cocci patients and controls or cells from specific knockout mice challenged with killed Coccidioides spherules, we will examine and shed light on the role of inflammasome and non- inflammasome mediated cleavage and release of IL-1 and IL-1 in the host response to Coccidioides infection. Aim 3. Investigate the contribution of activating and inhibitory receptors to inter-leukocyte shuttling of coccidioides endospores. We will investigate the control of Coccidioides endospore shuttling by activating and inhibitory receptors on mouse and human neutrophils, macrophages, and dendritic cells. The overall impact of this work will improve our understanding of the immune response to Coccidioides and improve our ability to predict outcomes in patients with coccidiomycosis.