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

CD8 T细胞免疫调控在弓形虫感染中的功能分析

• 批准号: 8090422
• 负责人: DAVID J BZIK
• 金额: $ 23.46万
• 依托单位: DARTMOUTH COLLEGE
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-01 至 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8090422
• 关键词: AIDS-Related Opportunistic Infections; Acquired Immunodeficiency Syndrome; Acute; Address; Antigens; Attenuated Vaccines; Biological; Biological Response Modifiers; Biology; Brain; CD8B1 gene; Chronic; Complex; Cyst; Data; Dissection; Dose; Encephalitis; Epitopes; Future; Genes; Human; Immune; Immune response; Immunity; Immunologic Surveillance; Individual; Infection; Infection prevention; Interferons; Intervention; Knock-out; Knowledge; Life; MHC Class I Genes; Maps; Measures; Mediating; Modeling; Mus; Opportunistic Infections; Outcome; Parasites; Patients; Population; Production; Pyrimidine; Reagent; Recrudescences; Recurrence; Research; Risk; Role; Rupture; T cell response; T-Lymphocyte; T-Lymphocyte Epitopes; Testing; Toxoplasma gondii; Toxoplasmosis; Vaccinated; Vaccination; Vaccine Design; Vaccines; Virulent; Work; improved; innovation; knockout gene; mutant; novel strategies; pathogen; prevent; public health relevance; research study; tool; vaccine development; vaccine-induced immunity

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).

描述（由申请人提供）：弓形虫Gondii是艾滋病患者的重要机会感染。迫切需要改进的策略和方法，以更有效地预防和治疗艾滋病中的复发感染。尽管广泛了解宿主对T. gondii感染的免疫反应，但尚未批准用于该寄生虫或任何其他原生动物寄生虫的疫苗，从而在艾滋病中引起机会感染。急性原发性感染后，在中枢神经系统/大脑中建立了慢性寿命T. gondii感染，这种慢性感染的特征在于持续存在包含缓慢复制的胸骨寄生虫形式的囊肿。由于慢性感染中脑囊肿破裂而导致的主动感染的重新激活是导致难以治疗和威胁生命的毒质性毒性脑炎的主要机制。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一个主要差距。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产生是急性原发性和慢性T. gondii感染中免疫控制的关键介体。我们假设对急性和慢性感染的免疫控制高度依赖于抗原特异性CD8+ T细胞群体，这些抗原特异性CD8+ T细胞种群识别在感染过程中呈现给MHC I类的特定寄生虫衍生的表位。该假设将通过研究定义的CD8+ T细胞表位的功能重要性在实验中介导对急性和慢性感染的控制中使用突变毒素菌株以及突变体衰减的疫苗菌株，而这些疫苗缺乏已知的内源性寄生虫衍生寄生虫衍生的CD8+ T细胞（S）。将确定定义的CD8+ T细胞表位在引发致命急性感染的保护性免疫中的功能重要性，以及正常预先建立的疫苗诱导的免疫力防止缺乏缺乏特异性寄生虫寄生虫衍生的CD8+ T细胞的毒性突变菌株（S）的能力（s）。这项创新的探索性研究将在功能上揭示四个最近鉴定出的且潜在的免疫寄生虫衍生的CD8+ T细胞表位及其相应的CD8+ T细胞群是否确定了急性和慢性T. gondii感染的免疫控制。该项目产生了重大影响，因为它与对急性和慢性感染的免疫控制有关的理解涉及，这将使将来的研究集中在最关键的寄生虫抗原及其抗原特异性CD8+ T细胞反应上。该项目也与改进疫苗设计有关，并确定新的干预措施以解决艾滋病中的慢性感染。 公共卫生相关性：该项目与了解艾滋病的机会性病原体弓形虫的免疫控制有关。目前尚无疫苗来防止感染，也没有可用于消除感染个体的慢性感染的治疗方法。通过解决该项目中Gondii感染中免疫控制的基本和功能方面，我们希望可以透露可直接应用于疫苗开发的新信息，以防止感染，并识别潜在的干预措施，以消除已经受到严重反复感染风险的已经受感染的人的慢性感染。