Cryptococcal Chitin Synthase 3 and Host Immune Responses

隐球菌几丁质合酶 3 和宿主免疫反应

• 批准号: 10055130
• 负责人: Camaron Reynolds Hole
• 金额: $ 16.2万
• 依托单位: UNIVERSITY OF TENNESSEE HEALTH SCI CTR
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-01 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10055130
• 关键词: Acquired Immunodeficiency Syndrome; Animals; Antibodies; Antifungal Therapy; Area; Basic Science; Biochemical; Biological Assay; Biology; Cell Wall; Cells; Cessation of life; Chitin; Chitin Synthase; Chitin deacetylase; Chitosan; Clinical; Cryptococcal Meningitis; Cryptococcosis; Cryptococcus; Cryptococcus gattii; Cryptococcus neoformans; Cryptococcus neoformans infection; Data; Diagnostic; Disease; Dose; Drug Costs; Exhibits; Failure; Foundations; Fungal Antigens; Fungal Components; Future; Goals; Hour; Immune; Immune response; Immune system; Immunity; Immunocompetent; In Vitro; Incubated; Infection; Inflammatory Response; Knowledge; Laboratories; Lead; Left; Lung; Mediating; Mentorship; Morbidity - disease rate; Mus; Mycoses; Neurologic; Organ Transplantation; Organism; Pathogenesis; Pathway interactions; Patients; Play; Positioning Attribute; Reporter; Research Personnel; Resolution; Resources; Role; Source; Testing; The science of Mycology; Toxic effect; Transplant Recipients; Vaccines; Virulent; Work; career; chemokine; combat; cytokine; experience; fungus; inhibitor/antagonist; insight; mortality; neutrophil; novel; pathogen; pathogenic fungus; pathogenic microbe; recruit; skills

PROJECT SUMMARY/ABSTRACT Cryptococcus neoformans infections are a significant cause of morbidity and mortality among AIDS patients and the third most common invasive fungal infection in organ transplant recipients. There are an estimated quarter million cases of cryptococcal meningitis each year resulting in ~200,000 deaths. Because host immune responses are so vital to the control of cryptococcosis, my long-term goal is to delineate the host: fungal interactions that impact C. neoformans pathogenesis or clearance. One of the main interfaces between the fungus and the host is the fungal cell wall. The cell wall in Cryptococcus is unusual in that the chitin is predominantly deacetylated to chitosan. Chitosan deficient strains of C. neoformans were found to be avirulent and were rapidly cleared from the murine lung. Moreover, infection with a chitosan deficient C. neoformans lacking three chitin deacetylases (cda1Δ2Δ3Δ) was found to confer protective immunity to a subsequent challenge with a virulent wild type counterpart. In addition to the chitin deacetylases, it was previously shown that chitin synthase 3 (Chs3) is also essential for chitin deacetylase mediated formation of chitosan. Mice inoculated with chs3Δ at a dose previously shown to induce protection with cda1Δ2Δ3Δ die within 36 hours after installation of the fungal organism. Death is dose dependent as mice given a lower dose did not succumb. Mortality was not dependent on viable fungi as mice inoculated with heat-killed chs3Δ died at the same rate as mice inoculated with live chs3Δ, suggesting that the rapid onset of death was host mediated likely caused by an over exuberant immune response. Altogether, these studies lead us to hypothesize that Chs3 plays a critical role in dampening cryptococcal induced host inflammatory responses. In this application we aim to define the mechanism(s) within the host that trigger the aberrant immune response to chs3Δ and identify the cellular component(s) from chs3Δ that elicit this non-protective pro-inflammatory response. The work proposed in this application will have significant overall impact on basic science knowledge, which will provide insights into other pathogenic microbes and areas of biology, as well as potentially advance our understanding of a significant problem in the management of cryptococcal patients. This K22 approach will provide me with opportunities to not only understand the pathways that drive the host response and the cryptococcal components that drive the immune response, but also the bifurcation between protective and non-protective innate host responses. The mentorship received in Drs. Wormley, Doering, and Lodge laboratories, as well as the knowledge and experiences gained has afforded me the skills and opportunities to become an independent researcher and to pursue a successful career studying host: pathogen interactions. This work will provide the foundation for future RO1 applications as well as a career investigating the host: fungal interactions that impact fungal pathogenesis or clearance.

项目摘要/摘要 艾滋病患者和 器官移植受体中第三大常见的浸润性真菌感染。有一个估计的季度 每年的隐球菌性脑膜炎病例数百万，导致约20万人死亡。因为宿主免疫 反应对控制隐球菌的控制至关重要，我的长期目标是描绘宿主：真菌 影响C. Neofors发病机理或清除率的相互作用。之间的主要接口之一 真菌和宿主是真菌细胞壁。加密环球中的细胞壁是不寻常的，因为几丁质是 主要脱乙酰化至壳聚糖。发现壳聚糖缺乏新生梭状芽胞杆菌是无毒的 并迅速从鼠肺中清除。此外，壳聚糖缺乏梭菌的感染 缺少三个几丁质脱乙酰基酶（CDA1Δ2δ3δ）会会象与随后的免疫力。 挑战有毒的野生型对应物。除了几丁质脱乙酰基酶外，先前还显示 壳蛋白合酶3（CHS3）对于壳蛋白脱乙酰基酶介导的壳聚糖的形成也是必不可少的。老鼠 接种 CHS3δ 先前显示的剂量以诱导CDA1Δ2δ3δ在36小时内死亡 真菌生物的安装。死亡是剂量依赖的，因为给定剂量较低的小鼠没有屈服。 死亡率不依赖于可行的真菌，因为被热杀死的小鼠接种 CHS3δ 死亡的速度与 接种活的CHS3δ的小鼠，表明死亡的快速发作是宿主的介导的，可能是由 过度旺盛的免疫反应。总之，这些研究使我们假设CHS3起着至关重要的作用 在DAMPOCCAL诱导的宿主炎症反应中。在此应用中，我们旨在定义 宿主内的机理，触发对CHS3δ的异常免疫反应并识别细胞的机理 CHS3δ的成分引起这种非保护促炎反应。提出的工作 应用将对基础科学知识产生重大影响，这将为其他人提供见解 致病微生物和生物学领域，并有可能提高我们对重要的理解 隐球菌患者管理中的问题。这种K22方法将为我提供机会 不仅了解驱动主机响应的途径和驱动驱动的加密局部组件 免疫反应，以及受保护和非保护先天宿主反应之间的分叉。 博士收到的脑海。蠕虫，doering和lodge实验室，以及知识和知识 获得的经验为我提供了成为独立研究人员的技能和机会 追求成功的职业研究主持人：病原体互动。这项工作将为未来提供基础 RO1应用以及调查主机的职业：影响真菌发病机理的真菌互动 或清除。