Protective Host Immunity Against Pulmonary Cryptoccoccosis

宿主对肺隐球菌病的保护性免疫

• 批准号: 8019452
• 负责人: Floyd L. Wormley
• 金额: $ 34.01万
• 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 2013-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8019452
• 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; HIV; Host Defense Mechanism; Immune; Immune response; Immune system; Immunity; Immunization; Individual; Infection; Inflammatory; Inflammatory Response; Interferon Type II; Interferons; 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（由申请人提供）：美国艾滋病毒感染个体中的隐孢子菌感染的发生率为5-10％，是艾滋病患者发病和死亡率的主要原因。研究表明，T Helper（Th）1型CD4+ T细胞的细胞介导的免疫（CMI）是针对新旋转梭菌感染的主要宿主防御机制。但是，尚未定义详细的免疫反应，该免疫反应会引起对隐球菌复发或再感染的保护。在我们的初步研究中，我们已经表明，在小鼠中使用干扰素伽马（IFN-G）产生新的C. Neoformans菌株的实验性肺部感染导致诱导Th1型CMI反应和急性感染的分辨率。此外，我们首次证明，产生IFN-G的新甲状腺梭菌菌株的先前挑战会导致（100％）对第二次肺部挑战的挑战，并具有致病性的Neoformans菌株。基于这些结果，我们假设为生产IFN-G而设计的Neofors菌株可用于确定针对致病性肺C. Neoformans感染的保护性宿主免疫的机制。因此，我们建议使用此模型系统使用以下“特定目的”来分析保护性抗癌宿主免疫反应：（1）表征局部加密摄氏IFN-G产生对诱导宿主免疫对肺隐孢子菌病的诱导的影响。 （2）确定负责与致病性梭菌菌株再感染的抗性的免疫机制。 （3）评估小鼠抗炎性反应的局部病理和细胞组成，并且易受实验性肺隐球菌病的影响。 （4）确定与IFN-G产生新构梭菌菌株的挑战途径是否会影响针对肺或新生梭菌感染的保护性免疫的发展。 Neoformans是一种机会性真菌，可能会导致抑制免疫系统的个体中威胁生命的大脑感染。我建议进行研究，以定义可以针对新甲状腺梭菌感染产生哪些保护性免疫反应的参数。我的期望是，这些研究将导致疗法和/或疫苗的发展，以治疗或预防免疫受损的个体中真菌感染。