Identification of C. neoformans proteins that induce protective immunity.

描述（由申请方提供）：新型隐球菌是隐球菌病的主要病原体，是一种真菌病原体，可在免疫受损宿主中引起危及生命的脑膜脑炎。目前的抗隐球菌药物疗法通常由于药物毒性、耐药生物体的出现和/或宿主的受抑制的免疫系统不能帮助解决疾病而变得无效。迄今为止，还没有疫苗或免疫疗法被批准用于治疗隐球菌病。迄今为止，使用各种蛋白质制剂或使用抗隐球菌单克隆抗体的血清疗法免疫小鼠的实验努力仅诱导了对随后的攻击的部分保护。我们实验室的研究表明，急性C。将工程化表达IFN-3的新型人菌株H99命名为C.新型人菌株H993，导致诱导有效的CD 4 + Th 1型细胞介导的免疫应答和感染的消退。此外，C. neoformans菌株H993，而不是热灭活的C.新型隐球菌，导致对随后在免疫活性和CD 4 + T细胞缺陷小鼠中用野生型隐球菌进行的致死性肺攻击的杀菌免疫。这些研究表明，诱导保护性抗C。免疫受损宿主中的新生儿免疫力确实是可实现的。因此，我们试图鉴定隐球菌蛋白候选物，其可用作亚单位疫苗的一部分，以诱导小鼠中针对隐球菌病的保护性CD 4 + Th 1型细胞介导的免疫（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隐球菌蛋白的复杂混合物，以寻找那些引发针对隐球菌的抗原特异性Th 1型细胞介导的免疫应答的蛋白质。本研究的主要目的是：（1）鉴定和鉴定C.新形式的蛋白质，诱导保护性Th 1型细胞介导的免疫应答。(2)评价C. neoformans蛋白诱导对实验性肺隐球菌病的保护。 公共卫生相关性：新型隐球菌是一种机会性真菌，可能导致免疫系统受抑制的个体发生危及生命的大脑感染。我建议进行研究，以确定和评估特定的C。neoformans蛋白质以诱导针对隐球菌感染的保护。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.