Host Immunogenetics and Fungal Virulence Mechanisms in Coccidioidomycosis

球孢子菌病的宿主免疫遗传学和真菌毒力机制

• 批准号: 10356724
• 负责人: MANISH J BUTTE
• 金额: $ 169.88万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-01-24 至 2026-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10356724
• 关键词: Address; Animal Model; Antifungal Agents; Area; B-Lymphocytes; California; Case Study; Cell Wall; Clinic; Clinical; Coccidioides; Coccidioidomycosis; Communication; Data; Defect; Development; Diagnosis; Diagnostic; Disease; Genetic; Genetic Transcription; Genomics; Goals; Helper-Inducer T-Lymphocyte; Host Defense; Human; Immune; Immune Evasion; Immune response; Immunity; Immunodominant Antigens; Immunogenetics; Immunologics; Immunologist; Inbred Strains Mice; Individual; Infection; Innate Immune Response; Institutes; Investigation; Life; Lung; Lung diseases; Measures; Membrane Lipids; Mucous Membrane; Mycoses; Natural Immunity; Organism; Outcome; Patients; Phagocytosis; Play; Predisposition; Prevention; Publishing; Reagent; Reproduction spores; Research; Research Personnel; Resistance; Role; Running; Safety; Sampling; Side; Signal Pathway; T-Lymphocyte; Variant; Virulence; Virulence Factors; adaptive immune response; adaptive immunity; clinical heterogeneity; cohesion; desert fever; experimental study; fungus; meetings; mouse model; multidisciplinary; novel strategies; pathogen; premature; prevent; prognostic; programs; rare variant; recruit; response; tool

There is a broad heterogeneity of clinical outcomes after infection with Coccidioides (Cocci) ranging from asymptomatic infection to mild pulmonary disease (“Valley fever”) to a life-threatening, invasive disease called disseminated coccidioidomycosis (DCM). Everyone in the endemic areas is susceptible to this infection, but we have almost no ability to predict who will develop disseminated disease and lack an understanding of why they do so. With nearly 10K reported cases of Valley fever and 200 cases of DCM yearly in California, our state alone spends ~$1B yearly on coccidioidomycosis. Thus, there is an urgent need to better understand DCM to enable better prevention, diagnostics, prognostics, and treatments. Our team's long-term goal is to study the intersection between the virulence programs of Coccidioides spp that maliciously exploit defective immunity, and the dysregulation of genetic and immunological programs of innate and adaptive immunity that allow for severe disease to take hold. Our program will bring together a cohesive and multi-disciplinary team of immunologists, geneticists, computational biologists, fungal microbiologists, and clinicians. Combining deep expertise with synergistic goals will enable breakthroughs. Our consortium includes four Projects and three supporting Cores: Project 1 addresses the innate immune responses to cocci infection that go awry in the first stages of cocci infection; Project 2 addresses the adaptive immune responses to cocci infection that go awry in protecting the host from disseminated disease; Project 3 addresses the genomic basis of cocci disease, from common variants that underlie susceptibility due to ancestry to rare variants that disable host defenses; and Project 4 addresses the contributions of fungal virulence factors in enabling the organisms to evade host immune defenses in some individuals. Our program includes an Administrative Core (Core A) that facilitates communications between investigators, organizes meetings and finances, and runs the Developmental Research Program. We also propose a unified Clinical Samples Core (Core B) comprising two of the largest coccidioidomycosis clinics in California, and a Model Organisms Core (Core C) that will carry out all experiments requiring BSL3 safety measures. These Cores together empower the proposed projects by providing common reagents, human samples, tools, and expertise. Our proposed investigations have the potential to transform our understanding of invasive fungal infections and will restore hope for patients through new approaches to prevent, diagnose, and treat DCM.

在感染球虫（COCCI）之后，临床结局的异质性广泛。 无症状感染对轻度肺部疾病（“山谷热”），危及生命的侵入性疾病 传播球菌病（DCM）。流行地区的每个人都容易受到这种感染的影响，但是我们 几乎没有能力预测谁会发展传播疾病，并且缺乏对他们为什么的理解 这样做。仅在加利福尼亚州，近10K报告了山谷发烧的病例和200例DCM病例，仅我们的州就 每年花费约1B $ 1B上的球菌病。那是迫切需要更好地理解DCM以启用 更好的预防，诊断，预后和治疗方法。我们团队的长期目标是研究 恶性探索有缺陷的免疫（和 先天性和适应性免疫学的遗传和免疫学计划的失调，允许严重 疾病要结束。 我们的计划将汇集一个具有凝聚力和多学科的免疫学家，遗传学家， 计算生物学家，真菌微生物学家和临床医生。将深厚的专业知识与协同目标相结合 将实现突破。 我们的财团包括四个项目和三个支持核心：项目1解决了先天免疫 对球球菌感染的第一阶段出现问题的反应；项目2解决了适应性 对球菌感染的免疫反应在保护宿主免遭传播疾病时出现问题；项目3 从基于祖先敏感的普通变体中解决了球菌疾病的基因组基础 对于禁用宿主防御的罕见变体；项目4解决了真菌病毒因素的贡献 使生物体能够逃避某些人的免疫防御能力。我们的计划包括一个 行政核心（核心A）促进调查人员之间的通信，组织会议和 财务并运行发展研究计划。我们还提出了一个统一的临床样品核心 （核B）包括加利福尼亚州最大的两家球虫菌病诊所，以及模型有机体核心 （核心C）将执行所有需要BSL3安全措施的实验。这些核心共同授权 提出的项目通过提供常见试剂，人类样品，工具和专业知识。 我们提出的调查有可能改变我们对侵入性真菌感染的理解 并将通过预防，诊断和治疗DCM的新方法来恢复患者的希望。