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: 10554360
• 负责人: MANISH J BUTTE
• 金额: $ 170.28万
• 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/10554360
• 关键词: Address; Antifungal Agents; Area; B-Lymphocytes; California; Case Study; Cell Wall; Clinic; Clinical; Coccidioides; Coccidioidomycosis; Communication; Data; Defect; Development; Diagnosis; Diagnostic; Disease; Ensure; 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; 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; desert fever; empowerment; experimental study; fungus; meetings; model organism; 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.

球孢子菌 (Cocci) 感染后的临床结果存在广泛的异质性，包括 无症状感染到轻度肺部疾病（“谷热”）到危及生命的侵袭性疾病，称为 播散性球孢子菌病（DCM）。流行地区的每个人都容易受到这种感染，但我们 几乎没有能力预测谁会患上传播性疾病，并且不了解为什么会患上传播性疾病 这样做。加利福尼亚州每年报告近 1 万例山谷热病例和 200 例 DCM 病例，仅我们州 每年在球孢子菌病上花费约 10 亿美元。因此，迫切需要更好地理解DCM以实现 更好的预防、诊断、预后和治疗。我们团队的长期目标是研究 恶意利用免疫缺陷的球孢子菌毒力程序之间的交叉点，以及 先天性和适应性免疫的遗传和免疫程序失调，导致严重的 疾病占据上风。 我们的项目将汇集一个由免疫学家、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。 我们的联盟包括四个项目和三个支持核心：项目 1 解决先天免疫问题 对球菌感染的反应在球菌感染的第一阶段出现问题；项目 2 解决了自适应问题 对球菌感染的免疫反应在保护宿主免受传播疾病方面出错；项目3 解决球菌疾病的基因组基础，从导致祖先易感性的常见变异开始 禁用宿主防御的罕见变体；项目 4 讨论了真菌毒力因子的贡献 使生物体能够逃避某些个体的宿主免疫防御。我们的计划包括 行政核心（核心 A），促进调查人员之间的沟通、组织会议和 资助并运行发展研究计划。我们还提出了统一的临床样本核心 （核心 B）包括加利福尼亚州最大的两个球孢子菌病诊所和一个模型生物核心 （核心 C）将执行需要 BSL3 安全措施的所有实验。这些核心共同赋予 通过提供通用试剂、人体样本、工具和专业知识来提议项目。 我们提出的研究有可能改变我们对侵袭性真菌感染的理解 并将通过预防、诊断和治疗 DCM 的新方法为患者重拾希望。