Protective Host Immunity Against Pulmonary Cryptoccoccosis

描述(申请人提供)：在美国，HIV感染者中的新生隐球菌感染的流行率为5%-10%，是导致艾滋病患者发病率和死亡率的主要真菌学原因。研究表明，辅助性T细胞(Th)1型CD4+T细胞介导的细胞免疫(CMI)是机体对新生葡萄球菌感染的主要防御机制。然而，引起对隐球菌复发或再感染的保护的详细免疫反应尚未确定。在我们的初步研究中，我们已经证明，在小鼠实验性肺部感染中，产生干扰素-g(IFN-g)的新生葡萄球菌株会导致Th1型CMI反应的诱导和急性感染的解决。此外，我们首次证明，用产生干扰素-g的新生芽孢杆菌菌株对第二次肺部攻击具有完全(100%)保护作用。根据这些结果，我们推测产生干扰素-g的新型弧菌可以用来确定其保护宿主免疫抵抗病原性肺部新生弧菌感染的机制(S)。因此，我们建议使用这个模型系统来分析保护性抗隐球菌宿主免疫反应，具有以下“特定目的”：(1)表征局部产生的隐球菌干扰素-g在诱导宿主对肺隐球菌病免疫中的影响。(2)确定抵抗致病性新生葡萄球菌再次感染的免疫机制(S)。(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和细胞组成。(4)确定对产生干扰素-g的新生葡萄球菌菌株的攻击途径是否影响对肺部或播散性新生葡萄球菌感染的保护性免疫的形成。新生隐球菌是一种机会性真菌，在免疫系统受到抑制的人中，可能会导致危及生命的脑部感染。我建议进行研究，以确定可以产生保护性免疫反应的参数，以对抗新生葡萄球菌感染。我的期望是，这些研究将导致治疗和/或疫苗的开发，以治疗或预防免疫受损个体的真菌感染。

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.