Parasite secreted proteins control host response to Toxoplasma gondii infection

寄生虫分泌的蛋白质控制宿主对弓形虫感染的反应

• 批准号: 8466449
• 负责人: DAVID J BZIK
• 金额: $ 20.2万
• 依托单位: DARTMOUTH COLLEGE
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-02-01 至 2015-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8466449
• 关键词: AIDS-Related Opportunistic Infections; Acquired Immunodeficiency Syndrome; Acute; Affect; Alleles; Amino Acids; Antigen-Presenting Cells; Antigens; Biological Assay; Biology; CD8B1 gene; Cell Communication; Cells; Chronic; Complement; Dendritic Cells; Development; Disease; Encephalitis; Epitopes; Genes; Goals; HIV Infections; Human; Hybridomas; Immune; Immune response; Immunity; Immunosuppression; Immunotherapy; In Vitro; Infection; Infection Control; Infection prevention; Knowledge; Lead; Life; MHC Class I Genes; Measures; Modeling; Outcome; Parasite Control; Parasites; Pathway interactions; Peptides; Pharmaceutical Preparations; Phenotype; Play; Population; Proteins; Recurrence; Role; Specificity; T cell response; T-Cell Development; T-Lymphocyte; Testing; Therapeutic Intervention; Toxoplasma gondii; Toxoplasmosis; Vaccines; Vacuole; Virulent; XRCC5 gene; cell type; cytotoxicity; improved; in vivo; innovation; loss of function; macrophage; mutant; novel; prevent; public health relevance; response; therapeutic vaccine

DESCRIPTION (provided by applicant): Toxoplasma gondii is a significant opportunistic infection of AIDS. T. gondii causes a common infection that develops into chronic life-long infection. Reactivated infection during immune suppression causes a difficult to treat and life-threatening Toxoplasmic encephalitis in AIDS. New strategies are needed to more effectively prevent and treat recurrent infections in AIDS. There is no vaccine or immunotherapy approved for use in humans and current drug treatments are suboptimal. Furthermore, T. gondii infection may influence the outcome of HIV infection and progression to AIDS. Eradicating chronic T. gondii infection is an excellent approach to control/prevent infection in AIDS, however, due to a lack of knowledge about T. gondii infection and host response no strategy is available today to achieve this goal. Immune control of acute and chronic T. gondii infection depends on the development of a protective CD8+ T cell response. We currently have limited knowledge of parasite and host mechanisms that determine priming of the protective CD8+ T cell response. T. gondii infected host cells, particularly infected antigen presenting cell types, such as dendritic cells and macrophages, play a major role in priming the protective CD8+ T cell response. Emerging evidence also points to parasite-secreted proteins as being central to mechanisms of host interaction and host cell manipulation by T. gondii. These observations lead us to hypothesize that parasite secreted proteins play a central role in controlling the priming of CD8+ T cell responses by infected antigen presenting cells. Consequently, we propose to examine the role of specific parasite secreted proteins from virulent type I strains (Aim 1) and chronic type II strains (Aim 2) in priming CD8+ T cells in vitro. Our model predicts that parasite-secreted proteins manipulate the ability of infected cells to prime CD8+ T cell responses. To test this hypothesis, we will measure the ability of host cells infected with type I or type II mutants that lack a specific secreted proein to prime CD8+ T cells. Aim 3 of this innovative R21 proposal will further examine the role of specific secreted proteins identified in Aim 1 and Aim 2 in ex vivo assays to further understand the mechanisms used by parasite secreted proteins to regulate the priming of natural CD8+ T cell populations during T. gondii infection. Collectively, these Aims will functionally identify parasite-secreted proteins that determine the protective host response and control or loss of control of infection, and will thus identify new targets as well as new strategies for therapeutic intervention. This innovative and exploratory R21 project will also illuminate fundamental aspects of parasite vacuole biology, host-parasite interactions, host cell manipulation, and host response during T. gondii infection.

描述（由申请人提供）： 弓形虫是艾滋病的一种重要机会性感染。弓形虫引起一种常见感染，并发展成慢性终身感染。免疫抑制过程中重新激活的感染会导致艾滋病中难以治疗且危及生命的弓形虫脑炎。需要新的策略来更有效地预防和治疗艾滋病的复发感染。目前还没有批准用于人类的疫苗或免疫疗法，并且目前的药物治疗效果不佳。此外，弓形虫感染可能会影响艾滋病毒感染的结果以及艾滋病的进展。根除慢性弓形虫感染是控制/预防艾滋病感染的极好方法，然而，由于缺乏对弓形虫感染和宿主反应的了解，目前尚无可用的策略来实现这一目标。急性和慢性弓形虫感染的免疫控制取决于保护性 CD8+ T 细胞反应的发展。目前，我们对决定保护性 CD8+ T 细胞反应启动的寄生虫和宿主机制了解有限。弓形虫感染的宿主细胞，特别是感染的抗原呈递细胞类型，如树突状细胞和巨噬细胞，在启动保护性 CD8+ T 细胞反应中发挥着重要作用。新出现的证据还表明，寄生虫分泌的蛋白质是弓形虫与宿主相互作用和宿主细胞操纵机制的核心。这些观察结果使我们推测寄生虫分泌蛋白在控制受感染抗原呈递细胞引发 CD8+ T 细胞反应方面发挥着核心作用。因此，我们建议研究来自强毒 I 型菌株（目标 1）和慢性 II 型菌株（目标 2）的特定寄生虫分泌蛋白在体外启动 CD8+ T 细胞中的作用。我们的模型预测寄生虫分泌的蛋白质可以操纵受感染细胞引发 CD8+ T 细胞反应的能力。为了检验这一假设，我们将测量感染 I 型或 II 型突变体（缺乏特定分泌蛋白）的宿主细胞启动 CD8+ T 细胞的能力。这项创新 R21 提案的目标 3 将进一步检查目标 1 和目标 2 中鉴定的特定分泌蛋白在离体测定中的作用，以进一步了解寄生虫分泌蛋白在 T 期间调节天然 CD8+ T 细胞群启动的机制。弓形虫感染。总的来说，这些目标将在功能上识别寄生虫分泌的蛋白质，这些蛋白质决定保护性宿主反应以及感染的控制或失控，从而确定新的靶点以及治疗干预的新策略。这一创新性和探索性的 R21 项目还将阐明寄生虫液泡生物学、宿主与寄生虫相互作用、宿主细胞操作和弓形虫感染期间宿主反应的基本方面。