Identification of C. neoformans proteins that induce protective immunity.

描述(申请人提供)：新生隐球菌，隐球菌病的主要病原体，是一种真菌病原体，在免疫受损的宿主中会导致危及生命的脑膜脑炎。目前的抗隐球菌药物治疗往往由于药物毒性、耐药生物的出现和/或宿主被抑制的免疫系统无法帮助解决疾病而无效。到目前为止，还没有被批准用于治疗隐球菌病的疫苗或免疫疗法。到目前为止，使用各种蛋白质制剂免疫小鼠的实验努力，或使用抗隐球菌单抗的血清疗法，对随后的攻击只产生了部分保护。我们实验室的研究表明，一株表达干扰素-3的新型弧菌H99株，被命名为H993株，急性感染可以诱导强大的CD4Th1型细胞免疫反应，并缓解感染。此外，用新生隐球菌株H993免疫，但不用热灭活的新生隐球菌免疫，在免疫能力强的和CD4T细胞缺陷的小鼠中，对随后用野生型隐球菌攻击的致命肺部的免疫产生灭菌免疫。这些研究表明，疫苗策略可以诱导保护性抗C。免疫受损宿主中的新生杆菌免疫确实是可以实现的。因此，我们试图确定可作为亚单位疫苗的一部分的候选隐球菌蛋白，以诱导小鼠保护性CD4 Th1型细胞介导免疫(CMI)，以对抗隐球菌病。因此，本文提出的研究使用蛋白质组学和免疫学相结合的方法来筛选隐球菌蛋白的复杂混合物，以寻找那些能够诱导抗原特异性的Th1型细胞介导的免疫反应的蛋白，其具体目的如下：(1)鉴定和表征诱导保护性Th1型细胞介导的免疫反应的新生隐球菌蛋白。(2)评价新生隐球菌蛋白对实验性肺隐球菌病的保护作用。 公共卫生相关性：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，以确定和评估特定的新生链球菌蛋白诱导对隐球菌感染的保护作用。我的期望是，这些研究将导致治疗或预防真菌感染的疗法和/或疫苗的开发。

DESCRIPTION (provided by applicant): Cryptococcus neoformans, the main causative agent of cryptococcosis, is a fungal pathogen that causes life- threatening meningoencephalitis in immune compromised hosts. Current anti-cryptococcal drug therapies are oftentimes rendered ineffective due to drug toxicity, the emergence of drug resistant organisms, and/or the inability of the host's suppressed immune system to aid in resolution of the disease. To date, there is no vaccine or immunotherapy approved for the treatment of cryptococcosis. Experimental efforts to immunize mice using various protein preparations or serum therapy using anti-cryptococcal monoclonal antibodies have thus far induced only partial protection against subsequent challenge. Studies in our laboratory have shown that an acute infection with a C. neoformans strain H99 engineered to express IFN-3, designated C. neoformans strain H993, results in the induction of potent CD4+ Th1-type cell-mediated immune responses and resolution of infection. Moreover, immunization with C. neoformans strain H993, but not heat-killed C. neoformans, results in sterilizing immunity against a subsequent lethal pulmonary challenge with wild-type cryptococci in immune competent and CD4+ T cell deficient mice. These studies suggest that a vaccine strategy to induce protective anti-C. neoformans immunity in immune compromised hosts is indeed achievable. Accordingly, we have sought to identify cryptococcal protein candidates that may be used as part of a subunit vaccine to induce protective CD4+ Th1-type cell-mediated immunity (CMI) against cryptococcosis in mice. Consequently, the studies proposed herein use a combined proteomic and immunological approach to screen complex mixtures of cryptococcal proteins for those proteins that elicit antigen-specific Th1-type cell-mediated immune responses against C. neoformans infection using the following Specific Aims: (1) To identify and characterize C. neoformans proteins that induce protective Th1-type cell-mediated immune responses. (2) To evaluate the efficacy of C. neoformans proteins to induce protection against experimental pulmonary cryptococcosis. PUBLIC HEALTH RELEVANCE: 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 identify and evaluate the efficacy of specific C. neoformans proteins to induce protection against cryptococcal infections. My expectation is that these studies will lead to the development of therapies and/or vaccines to treat or prevent fungal infections.