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: 8605518
• 负责人: DAVID J BZIK
• 金额: $ 24.3万
• 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/8605518
• 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。T.弓形虫引起一种发展成慢性终身感染的常见感染。在免疫抑制期间的再活化感染导致艾滋病中难以治疗且危及生命的弓形虫脑炎。需要新的战略来更有效地预防和治疗艾滋病复发感染。目前还没有批准用于人类的疫苗或免疫疗法，而且目前的药物治疗也不理想。此外，T.弓形虫感染可能影响HIV感染的结局和向AIDS的进展。根除慢性T.弓形虫感染是控制/预防艾滋病感染的一个很好的方法，然而，由于缺乏对弓形虫的认识，弓形虫感染和宿主反应目前还没有实现这一目标的策略。急性和慢性T.弓形虫感染依赖于保护性CD 8 + T细胞应答的发展。我们目前对决定启动保护性CD 8 + T细胞应答的寄生虫和宿主机制的了解有限。T.弓形虫感染的宿主细胞，特别是感染的抗原呈递细胞类型，如树突细胞和巨噬细胞，在引发保护性CD 8 + T细胞应答中起主要作用。新出现的证据也指出寄生虫分泌的蛋白质是宿主相互作用和T.刚地。这些观察结果使我们假设寄生虫分泌的蛋白质在控制感染的抗原呈递细胞引发CD 8 + T细胞应答中起核心作用。因此，我们建议检查特定的寄生虫分泌蛋白的作用，从毒力I型菌株（目标1）和慢性II型菌株（目标2）在启动CD 8 + T细胞在体外。我们的模型预测，寄生虫分泌的蛋白质操纵感染细胞的能力，以引发CD 8 + T细胞反应。为了验证这一假设，我们将测量感染了缺乏特异性分泌蛋白的I型或II型突变体的宿主细胞引发CD 8 + T细胞的能力。这项创新的R21提案的目的3将进一步检查目的1和目的2中鉴定的特异性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细胞活化期间调节天然CD 8 + T细胞群体的启动的机制。弓形虫感染总的来说，这些目标将在功能上鉴定决定保护性宿主反应和感染控制或失控的寄生虫分泌蛋白，从而鉴定新的靶标以及治疗干预的新策略。这个创新和探索性的R21项目还将阐明寄生虫液泡生物学，宿主-寄生虫相互作用，宿主细胞操作和T.弓形虫感染