Control of cryptococcal infection through manipulation of the host immune response.

通过操纵宿主免疫反应来控制隐球菌感染。

• 批准号: 9198749
• 负责人: Kirsten Nielsen
• 金额: $ 19.06万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-01-01 至 2018-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9198749
• 关键词: Acute; Acute Disease; Affect; Antifungal Agents; Antigen Presentation; Antigen-Presenting Cells; Antigens; Brain; Breathing; CD4 Positive T Lymphocytes; Cells; Cellular Immunity; Cessation of life; Childhood; Coccidioides; Complex; Cryptococcus; Cryptococcus neoformans; Cryptococcus neoformans infection; Data; Defect; Dendritic Cells; Development; Disease; Exposure to; Foundations; Future; Gene Expression; Goals; HIV Infections; Histocompatibility; Histoplasma capsulatum; Hospitalization; Host Defense; Human; Immune; Immune response; Immune system; Immunity; Immunocompromised Host; Immunologics; In Vitro; Individual; Infection; Infection Control; Innate Immune Response; Interferon Type II; Interferons; Intervention; Knockout Mice; Life; Lung; Mediating; Mediator of activation protein; Medical; Meningitis; Modeling; Molecular; Mus; Mycoses; Natural Immunity; Neuraxis; Organism; Patient risk; Patients; Pharmacotherapy; Play; Pneumocystis; Population; Production; Property; Public Health; Research; T cell differentiation; T cell response; T-Cell Depletion; T-Lymphocyte; T-Lymphocyte Subsets; Testing; Transgenic Mice; base; cell type; chemokine; coping mechanism; cytokine; early childhood; experimental study; fungus; latent infection; mouse model; novel; novel strategies; pathogen; patient population; prevent; public health relevance; reconstitution; response; tool; transcription factor

 DESCRIPTION (provided by applicant): Only a handful of fungal species commonly cause disease in humans, making it easy to overlook their threat to public health, yet invasive fungal infections account for 22 of every 100,000 hospitalizations. Thus, fungi are robust pathogens that often establish lifelong infections in humans and can cause life-threatening disease, particularly in immune-compromised individuals. The fungus Cryptococcus neoformans commonly causes life- threatening meningitis in immune-compromised individuals, resulting in more than 650,000 deaths annually. Exposure to C. neoformans in early childhood results in an initial pulmonary infection that is controlled (latent), indicating that our immune system has effective mechanisms for coping with the infection and preventing disease. When the immune system fails, due to HIV infection or medical interventions that suppress immunity, this immune control is lost and the latent C. neoformans infection disseminates to the central nervous system to cause meningitis. Thus, a primary focus of this research application is to investigate the cellular and molecular basis for host control of C. neoformans in order to identify the "holes" in immune-mediated host defenses that are critical for the development of disease in immune-compromised individuals and that must be filled to prevent disease in at-risk patient populations. Most fungal infections, including cryptococcosis, are associated with diseases or medical interventions that affect cell mediated immunity - particularly CD4 T-cell mediated immunity. Given the vast immunological tools currently available in mice to study the priming and function of CD4 T-cell subsets, we developed a mouse inhalation model of latent cryptococcal infection. Using this model, we find infection is controlled by CD4 T-cell mediated immunity - mice only develop disease upon T-cell depletion. Therefore, our first aim is to identify the T-cell subsets, and their intrinsic properties, that control the cryptococcal infection. In our second aim, we will define the host and pathogen mediators of the T-cell response by testing the working hypothesis that differential activity of dendritic cell subsets primes beneficial T-cell responses that contro infection, in contrast to detrimental responses that promote disease. These studies will lay the foundation for future research to define the critical T-cell actions that prevent disease, determin why the immune response is unable to eradicate many fungal infections (resulting in latency), and identify novel strategies for immune modulatory or preferential replacement/reconstitution of essential T-cell populations in at-risk patient populations.

 描述（由申请人提供）：只有少数真菌物种通常会导致人类疾病，这使得人们很容易忽视它们对公共卫生的威胁，但侵袭性真菌感染占每10万例住院病例中的22例。因此，真菌是强大的病原体，经常在人类中建立终身感染，并可能导致危及生命的疾病，特别是在免疫受损的个体中。真菌新型隐球菌通常会在免疫受损的个体中引起危及生命的脑膜炎，每年导致超过65万人死亡。暴露于C。新生儿早期感染导致最初的肺部感染，这是控制（潜伏），表明我们的免疫系统有有效的机制来应对感染和预防疾病。当免疫系统由于HIV感染或抑制免疫力的医学干预而失败时，这种免疫控制丧失，潜伏的C。新型脑膜炎病毒会扩散至中枢神经系统，引致脑膜炎。因此，本研究应用的主要焦点是研究宿主控制C.新生儿，以便鉴定免疫介导的宿主防御中的“漏洞”，所述漏洞对于免疫受损个体中疾病的发展是关键的，并且必须被填补以预防处于风险中的患者群体中的疾病。大多数真菌感染，包括隐球菌病，与影响细胞介导的免疫-特别是CD 4 T细胞介导的免疫的疾病或医疗干预有关。鉴于目前在小鼠中可用于研究CD 4 T细胞亚群的启动和功能的大量免疫学工具，我们开发了潜伏隐球菌感染的小鼠吸入模型。使用这个模型，我们发现感染是由CD 4 T细胞介导的免疫控制的-小鼠只有在T细胞耗竭时才会发病。因此，我们的第一个目标是确定T细胞亚群及其内在特性，控制隐球菌感染。在我们的第二个目标中，我们将 通过测试树突细胞亚群的差异活性引发控制感染的有益T细胞应答而不是促进疾病的有害应答的工作假设，来定义T细胞应答的宿主和病原体介体。这些研究将为未来的研究奠定基础，以确定预防疾病的关键T细胞作用，确定为什么免疫反应无法根除许多真菌感染（导致潜伏期），并确定免疫调节或优先替代/重建高危患者人群中必需T细胞群的新策略。