Molecular and cellular analysis of host response to Cocci

项目2寄主对球孢子虫反应的分子和细胞分析 项目摘要 在项目2中，我们将应用复杂的技术来询问宿主对球虫的反应。 球虫感染导致一系列疾病结局，从亚临床感染到 社区获得性肺炎，到播散性中枢神经系统疾病。据推测， 宿主反应的变化，包括先天和/或获得性免疫反应的潜在差异， 对疾病表现的谱系有贡献。项目2的长期目标是应用转录组学， 用质量细胞术、单细胞RNAseq和噬菌体展示来分析分子和细胞对 使用体外感染模型和患者样本进行球虫感染。 我们的目标是研究东道主在三个关键领域的反应，这三个领域受益于专业知识和 调查人员可以利用的资源。我们将建立巨噬细胞对 通过比较这些宿主细胞与野生型或野生型感染的转录图谱 无毒球虫菌株(后者产生于CRISPR和毒力核心)。描述和描述 比较人类对慢性感染的反应，我们将使用质量细胞术和单细胞RNAseq来 询问加州流行区山谷热病患者的肺结节。这些研究将是 对大多数调查人员来说具有挑战性，并通过以下地址提供的复杂基础设施成为可能 加州大学旧金山分校的Colabs(见支持信)。此外，我们将利用一套丰富的临床样本 (来自加州大学戴维斯分校，项目3和临床和诊断核心)，以分析患者的脑脊液(CSF) 患有播散性球虫性脑膜炎。此外，为了确定主机响应的哪些元素可以 用于诊断应用，我们将使用高分辨率表位映射技术来识别 球虫蛋白质组的大多数免疫原区。值得注意的是，这个项目将吸引新的调查人员 球孢子菌病领域。综上所述，我们希望扩大我们对分子和细胞 球孢子虫感染的寄主反应成分，为球孢子虫的发育提供了重要的基础 未来的诊断和治疗。

Project 2 Molecular and Cellular Analysis of Host Response to Coccidioides Project Summary In project 2, we will apply sophisticated technologies to interrogate the host response to Coccidioides. Coccidioides infections cause a broad range of disease outcomes ranging from subclinical infection to a community-acquired pneumonia, to disseminated central nervous system disease. It has been postulated that variation in the host response, including potential differences in innate and/or adaptive immune responses, contributes to the spectrum of disease manifestations. The long-term goal of Project 2 is to apply transcriptomics, mass cytometry, single-cell RNAseq, and phage display to analyze the molecular and cellular response to Coccidioides infection using both in vitro infection models and patient samples. Our goal is to examine the host response in three critical areas that benefit from the expertise and resources available to the investigators. We will establish a baseline profile of the macrophage response to Coccidioides by comparing the transcriptional profile of these host cells to infection with either wild-type or avirulent Coccidioides strains (the latter generated in the CRISPR and Virulence Core). To characterize and compare the human response to chronic infection we will use mass cytometry and single-cell RNAseq to interrogate lung nodules from Valley Fever patients in the endemic region of California. These studies would be challenging for most investigators and are made possible here by the sophisticated infrastructure available at the UCSF CoLabs (see letter of support). Additionally, we will take advantage of a rich set of clinical samples (from UC Davis, Project 3 and Clinical and Diagnostics Core) to profile cerebrospinal fluid (CSF) from patients with disseminated coccidioidal meningitis. Additionally, to determine which elements of the host response can be utilized for diagnostic applications, we will use high-resolution epitope-mapping technology to identify the most immunogenic regions of the Coccidioides proteome. Notably this project will draw new investigators into the coccidioidomycosis field. Taken together, we hope to amplify our understanding of the molecular and cellular constituents of the host response to Coccidioides infection, providing a critical foundation for the development of future diagnostics and therapeutics.