Identification of C. neoformans proteins that induce protective immunity.

描述（由申请人提供）：隐球菌是隐球菌病的主要病原体，是一种真菌病原体，可在免疫功能低下的宿主中引起危及生命的脑膜脑炎。目前的抗隐球菌药物治疗通常由于药物毒性、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。迄今为止，还没有批准用于治疗隐球菌病的疫苗或免疫疗法。使用各种蛋白质制剂或使用抗隐球菌单克隆抗体的血清治疗对小鼠进行免疫的实验努力迄今为止仅诱导了对后续攻击的部分保护。我们实验室的研究表明，用表达IFN-3的新型C.菌株H99（命名为新型C.菌株H993）进行急性感染，可以诱导有效的CD4+ th1型细胞介导的免疫反应和感染的解决。此外，在免疫正常小鼠和CD4+ T细胞缺陷小鼠中，用新生隐球菌H993株免疫，而不是热杀新生隐球菌免疫，可对随后由野生型隐球菌引起的致死性肺部攻击产生无菌免疫。这些研究提示了一种诱导保护性抗- c抗体的疫苗策略。在免疫功能受损的宿主中，新形体的免疫确实是可以实现的。因此，我们试图鉴定隐球菌候选蛋白，这些候选蛋白可能用作亚单位疫苗的一部分，以诱导小鼠对隐球菌病的保护性CD4+ th1型细胞介导免疫（CMI）。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复杂的隐球菌蛋白混合物，以寻找那些引发抗原特异性th1型细胞介导的免疫反应的蛋白，以对抗新生隐球菌感染，其具体目的如下：(1)鉴定和表征诱导保护性th1型细胞介导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。

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.