Protective Host Immunity Against Pulmonary Cryptoccoccosis

宿主对肺隐球菌病的保护性免疫

• 批准号: 7587322
• 负责人: Floyd L. Wormley
• 金额: $ 34.7万
• 依托单位: UNIVERSITY OF TEXAS SAN ANTONIO
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-03-01 至 2012-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7587322
• 关键词: Acquired Immunodeficiency Syndrome; Acute; Biological Models; Brain; CD4 Positive T Lymphocytes; Cellular Immunity; Cryptococcus neoformans; Cryptococcus neoformans infection; Development; Engineering; Generations; Goals; Host Defense Mechanism; Immune; Immune response; Immune system; Immunity; Immunization; Individual; Infection; Inflammatory; Inflammatory Response; Interferon Type II; Intravenous; Lead; Life; Lung; Macrophage Activation; Morbidity - disease rate; Mus; Mycoses; Patients; Prevalence; Production; Relapse; Research Personnel; Resistance; Resolution; Route; Tetracyclines; Time; United States; Vaccines; Virulent; base; cellular pathology; expectation; fungus; in vivo; intraperitoneal; mortality; prevent; programs; response; secondary infection; therapy development

DESCRIPTION (provided by applicant): Cryptococcus neoformans infections among HIV-infected individuals in the United States occurs at a prevalence rate of 5-10% and is a leading mycological cause of morbidity and mortality among AIDS patients. Studies have suggested that cell-mediated immunity (CMI) by T helper (Th) 1-type CD4+ T cells is the predominant host defense mechanism against C. neoformans infections. However, the detailed immunological response that would elicit protection against cryptococcal relapse or reinfection is yet to be defined. In our preliminary studies, we have shown that an experimental pulmonary infection with an interferon gamma (IFN-g)-producing C. neoformans strain in mice results in the induction of Th1-type CMI responses and resolution of the acute infection. Furthermore, we have for the first time demonstrated that prior challenge with an IFN-g-producing C. neoformans strain results in complete (100%) protection against a second pulmonary challenge with a pathogenic C. neoformans strain. Based on these results, we hypothesize that C. neoformans strains engineered to produce IFN-g can be used to determine the mechanism(s) involved in protective host immunity against pathogenic pulmonary C. neoformans infections. Therefore, we propose to use this model system to analyze protective anti-cryptococcal host immune responses using the following "Specific Aims": (1) To characterize the impact of local cryptococcal IFN-g production on the induction of host immunity against pulmonary cryptococcosis. (2) To determine the immune mechanism(s) that is responsible for resistance against re-infection with a pathogenic C. neoformans strain. (3) To evaluate the local pathology and cellular composition of the inflammatory response in mice resistant and susceptible to experimental pulmonary cryptococcosis. (4) To determine if the route of challenge with the IFN-g producing C. neoformans strain influences the development of protective immunity against pulmonary or disseminated C. neoformans infections. Cryptococcus neoformans is an opportunistic fungus that may cause life-threatening infections of the brain in individuals with suppressed immune systems. I am proposing to perform studies to define the parameters of which protective immune responses can be generated against C. neoformans infections. My expectation is that these studies will lead to the development of therapies and/or vaccines to treat or prevent fungal infections in immune compromised individuals.

描述（由申请方提供）：在美国，HIV感染者中的新型隐球菌感染的患病率为5-10%，是AIDS患者发病和死亡的主要真菌原因。研究表明，辅助性T细胞（Th）1型CD 4 + T细胞介导的细胞免疫（CMI）是宿主抵抗C.新型感染。然而，详细的免疫反应，将引起对隐球菌复发或再感染的保护尚未确定。在我们的初步研究中，我们已经表明，实验性肺部感染与干扰素γ（IFN-g）产生的C。在小鼠中的新形式毒株的感染导致诱导Th 1型CMI应答和急性感染的消退。此外，我们首次证明了先前用产生IFN-g的C.新型梭菌菌株导致完全（100%）保护免受致病性梭菌的第二次肺攻击。neoformans菌株。基于这些结果，我们假设C。经工程改造以产生IFN-γ的新生菌菌株可用于确定保护性宿主免疫抵抗致病性肺念珠菌的机制。新型感染。因此，我们建议使用该模型系统来分析保护性抗隐球菌宿主免疫应答，具有以下“特定目的”：（1）表征局部隐球菌IFN-g产生对诱导抗肺隐球菌病的宿主免疫的影响。(2)确定抵抗致病性C. neoformans菌株。(3)评价实验性肺隐球菌病耐药和易感小鼠炎症反应的局部病理学和细胞组成。(4)为确定IFN-γ产生菌的攻毒途径是否可行。新型念珠菌株影响对肺部或播散性念珠菌的保护性免疫的发展。新型感染。新型隐球菌是一种机会性真菌，可能导致免疫系统受抑制的个体发生危及生命的脑部感染。我建议进行研究，以确定可以产生针对C的保护性免疫应答的参数。新型感染。我的期望是，这些研究将导致开发治疗或预防免疫受损个体真菌感染的疗法和/或疫苗。