Functional analysis of CD8 T cell immune control in Toxoplasma gondii infection

描述（申请人提供）：刚地弓形虫是艾滋病患者重要的机会性感染。迫切需要改进战略和方法，以更有效地预防和治疗艾滋病复发性感染。尽管对弓形虫感染的宿主免疫反应有广泛的了解，但目前还没有批准用于人类的疫苗，用于治疗这种寄生虫或引起艾滋病机会性感染的任何其他原生动物寄生虫。急性原发性感染后，慢性终身弓形虫感染在中枢神经系统/大脑中建立，这种慢性感染的特征是持续存在含有缓慢复制的慢殖虫寄生虫形式的囊肿。慢性感染时脑囊肿破裂引起活动性感染的再激活是导致艾滋病患者出现难以治疗且危及生命的弓形虫脑炎的主要机制。我们对控制急性感染和慢性感染的抗原特异性免疫因子的理解存在重大差距。我们的初步数据表明，CD8+ T细胞控制急性感染，并防止慢性感染中的囊肿破裂。CD8+ T细胞和IFN-3的产生是急性原发性和慢性弓形虫感染免疫控制的关键介质。我们假设急性和慢性感染的免疫控制高度依赖抗原特异性CD8+ T细胞群，这些细胞群识别在感染期间呈递给MHC I类的特定寄生虫来源的表位。这一假设将通过研究定义的CD8+ T细胞表位在介导急性和慢性感染控制中的功能重要性来验证，实验使用突变毒株和突变减毒疫苗株，这些毒株缺乏已知的内源性寄生虫来源的CD8+ T细胞表位。确定的CD8+ T细胞表位在引发对致命急性感染的保护性免疫中的功能重要性，以及通常预先建立的疫苗诱导免疫对缺乏特异性寄生虫来源的CD8+ T细胞表位的毒力突变株的保护能力将被确定。这项创新的探索性研究将从功能上揭示最近发现的四种潜在的免疫优势寄生虫来源的CD8+ T细胞表位及其相应的CD8+ T细胞群是否决定了急性和慢性弓形虫感染的免疫控制。该项目具有重要的影响，因为它与理解急性和慢性感染的免疫控制有关，这将使未来的研究重点放在最关键的寄生虫抗原及其抗原特异性CD8+ T细胞反应上。该项目还与改进疫苗设计和确定新的干预措施以解决艾滋病慢性感染有关。

DESCRIPTION (provided by applicant): Toxoplasma gondii is an important opportunistic infection of AIDS patients. Improved strategies and approaches are urgently needed to more effectively prevent and treat recurrent infections in AIDS. Despite extensive knowledge of host immune response to T. gondii infection, no vaccine is yet approved for use in humans for this parasite or any other protozoan parasite causing opportunistic infection in AIDS. Following an acute primary infection, a chronic life-long T. gondii infection is established in CNS/brain and this chronic infection is characterized by the persisting presence of cysts containing slowly replicating bradyzoite parasite forms. Reactivation of active infection due to rupture of brain cysts in chronic infection is the major mechanism causing difficult to treat and life-threatening Toxoplasmic encephalitis in AIDS. A major gap exists in our understanding of the antigen-specific immune factors that control acute infection and chronic infection. Our preliminary data shows that CD8+ T cells control acute infection and prevent cyst rupture in chronic infection. CD8+ T cells and IFN-3 production are critical mediators of immune control in acute primary and chronic T. gondii infection. We hypothesize that immune control of acute and chronic infection is highly dependent on antigen-specific CD8+ T cell populations that recognize specific parasite-derived epitopes presented to MHC class I during infection. This hypothesis will be tested by investigating the functional importance of defined CD8+ T cell epitopes in mediating control of acute and chronic infection in experiments using mutant virulent strains as well as mutant attenuated vaccine strains that lack known endogenous parasite-derived CD8+ T cell epitope(s). The functional importance of defined CD8+ T cell epitopes in eliciting protective immunity to lethal acute infection will be determined, as well as the ability of a normally pre-established vaccine-induced immunity to protect against a virulent mutant strain lacking specific parasite-derived CD8+ T cell epitope(s). This innovative and exploratory study will functionally reveal whether any of the four recently identified and potentially immunodominant parasite-derived CD8+ T cell epitopes and their corresponding CD8+ T cell populations determine the immune control of acute and chronic T. gondii infection. This project offers significant impact as it is relevant to the understanding of immune control of acute and chronic infection, which will allow future studies to focus on the most critical parasite antigens and their antigen-specific CD8+ T cell responses. This project is also is relevant for the improvement of vaccine design and to identify new interventions to address chronic infection in AIDS. PUBLIC HEALTH RELEVANCE: This project is relevant to understanding immune control of acute and chronic infection in the AIDS opportunistic pathogen Toxoplasma gondii. No vaccine is currently available to prevent infection, and no treatment is available to eradicate chronic infection in infected individuals. By addressing fundamental and functional aspects of immune control in T. gondii infection in this project, we expect to reveal new information that can be directly applied to vaccine development to prevent infection, as well as to identify potential interventions to eliminate chronic infection in already infected people who are particularly at risk of serious recurrent infection(s).