Protective Host Immunity Against Pulmonary Cryptoccoccosis

描述（由申请人提供）：在美国hiv感染者中，新型隐球菌感染的患病率为5-10%，是艾滋病患者发病和死亡的主要真菌学原因。研究表明，T辅助（Th） 1型CD4+ T细胞的细胞介导免疫（CMI）是主要的宿主防御新形梭菌感染的机制。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，在小鼠中使用干扰素γ (IFN-g)产生的新生C.菌株进行实验性肺部感染可诱导th1型CMI反应并解决急性感染。此外，我们首次证明，先前用产生ifn -g的新生C. formans菌株攻击可完全（100%）保护新生C. formans菌株免受致病性新生C. formans菌株的第二次肺部攻击。基于这些结果，我们假设，设计产生IFN-g的新生C.菌株可用于确定保护性宿主免疫对抗致病性肺新生C.感染的机制。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反应，并采用以下“特定目的”：(1)表征局部隐球菌IFN-g产生对诱导宿主免疫抗肺隐球菌病的影响。(2)确定对致病性新生芽胞杆菌再次感染产生抗性的免疫机制。(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)确定产生IFN-g的新生C.菌株的攻击途径是否影响对肺部或播散性新生C.感染的保护性免疫的发展。新型隐球菌是一种机会性真菌，可导致免疫系统受到抑制的个体发生危及生命的脑部感染。我建议开展研究，以确定可产生针对新生梭状菌感染的保护性免疫反应的参数。我的期望是，这些研究将导致治疗和/或疫苗的发展，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.