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.

感染球虫(Cocci)后的临床结果存在广泛的异质性，范围从 无症状感染到轻微的肺部疾病(“谷热”)，再到一种威胁生命的侵袭性疾病，称为 播散性球孢菌病(DCM)。流行区的每个人都容易感染这种病毒，但我们 几乎没有能力预测谁会患上播散性疾病，也不了解为什么 就这么做吧。仅在我们州，加利福尼亚州每年就有近10000例山谷热病例和200例DCM病例 每年在球孢子菌病上花费约10亿美元。因此，迫切需要更好地了解DCM以实现 更好的预防、诊断、预测和治疗。我们团队的长期目标是研究 球孢子虫恶意利用缺陷免疫的毒力程序之间的交叉，以及 先天性免疫和获得性免疫的遗传和免疫程序的失调，允许严重的 疾病肆虐。 我们的计划将汇聚一支由免疫学家、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 将实现突破性进展。 我们的联盟包括四个项目和三个支持核心：项目1涉及先天免疫 对在球菌感染的第一阶段出错的球菌感染的反应；项目2处理适应性 对在保护宿主免受播散性疾病侵袭过程中出错的球菌感染的免疫反应；项目3 阐述了球菌性疾病的基因组基础，以及源于血统易感性的常见变异。 到使宿主防御失效的罕见变异；项目4解决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。我们的计划包括一个 行政核心(核心A)，促进调查人员之间的沟通，组织会议和 为发展研究项目提供资金并运行该项目。我们还提出了一个统一的临床样本核心 (核心B)由加利福尼亚州两个最大的球孢子菌病诊所和一个模拟生物核心组成 (核心C)将执行需要BSL3安全措施的所有试验。这些核心共同支持 通过提供通用试剂、人体样本、工具和专业知识，拟议的项目。 我们提议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的新方法恢复患者的希望。