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Host Responses to Coccidioides by Human Airway Epithelium

人体气道上皮对球孢子菌的宿主反应

基本信息

批准号：
10616716
负责人：
Jatin M Vyas
金额：
$ 21万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-05-02 至 2025-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10616716
关键词：
Address Animals Antifungal Antibiotics Apical Architecture Attenuated CRISPR screen Cell Communication Cell Culture Techniques Cell Line Cell secretion Cells Clustered Regularly Interspaced Short Palindromic Repeats Coccidioides Coccidioides immitis Coccidioides posadasii Complication Critical Pathways Data Direct Costs Disease Dissection Distal Environment Epithelial Cells Epithelium Extravasation Foundations Future Gene Expression Profile Genetic Transcription Host Defense Human Human body IL8 gene Immune Immune response Immunity Immunocompetent Immunocompromised Host Immunologics Individual Infection Inflammation Mediators Inflammatory Inhalation Innate Immune Response Investigation Knowledge Life Cycle Stages Lung Lung infections Mediating Methodology Modeling Monitor Mus Mycoses Natural Resistance Pathogenicity Pathway interactions Patients Phagocytosis Play Proteins Response Elements Sampling Signal Induction Signal Pathway Signal Transduction Site Soil Sputum Surface System T cell response Tissues Transgenic Organisms United States Work airway epithelium biosafety level 3 facility chemokine cytokine experimental study fungus genome-wide in vivo innovation insight knockout gene lentiviral-mediated mortality mouse model new technology novel pathogen pathogenic fungus recruit response single-cell RNA sequencing stem cells transcriptome transcriptomics vaccine candidate

项目摘要

PROJECT SUMMARY Invasive fungal infections represent a major threat to immunocompromised patients and despite the availability of anti- fungal antibiotics, mortality rates remain as high as 50%. In the human host, the airway epithelium is the first point of contact upon inhalation of fungal conidia. As an immunologically active tissue, the airway epithelium may participate in active phagocytosis and coordinated immune cell recruitment. Soil fungi, including Coccidioides, do not need a human host to propagate, but upon disruption can enter the human body and lead to infection if not cleared. The fungal dimorph Coccidioides is native to arid regions in the southwestern U.S. and can establish infections in both immunocompetent and immunocompromised individuals. Unfortunately, little is known with regards to the initial response of human airway epithelium to Coccidioides. Currently, the Δcps1 strain of Coccidioides is being investigated as a potential vaccine candidate. Leveraging new technologies that permit the isolation of human airway stem cells, we demonstrated that primary differentiated human airway epithelial cells recapitulate the complexity of human airways. Our preliminary data showed infection at the apical surface of human airway epithelial cells by C. posadasii (Δcps1) elicits pro-inflammatory signals by the epithelium. Lastly, we demonstrated effective gene knockout in primary human airway epithelial cells using non-viral bulk nucleofection-based CRISPR strategy. Thus, our primary objective is to decipher the transcriptional and secretomal signatures critical to mount a successful response to Coccidioides in the human airway epithelium. To address our primary objective, we propose the following two specific aims: [1] determine the host response of human airway epithelium to both WT and the vaccine candidate C. posadasii (Δcps1), and [2] identify key signaling pathways to elicit an immune response to WT and the vaccine candidate C. posadasii (Δcps1) by human airway epithelium. This work will identify essential components of the human airway epithelium to mediate a protective response to these fungal infections and will provide the necessary foundation for future experiments to dissect the key pathways responsible for an effective host response to C. posadasii.

项目总结