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Gondii是艾滋病的重大机会感染。 T. gondii会引起常见感染，该感染发展为慢性寿命感染。免疫抑制期间重新激活的感染会导致难以治疗和威胁生命的艾滋病毒性脑炎。需要采取新的策略来更有效地预防和治疗艾滋病中的复发感染。没有批准用于人类的疫苗或免疫疗法，目前的药物治疗是次优的。此外，T。gondii感染可能会影响HIV感染和艾滋病的进展。消除慢性巨霉菌感染是控制/防止艾滋病感染的一种极好的方法，但是，由于缺乏对弓形虫感染的知识和宿主反应的了解，今天没有任何策略可以实现这一目标。急性和慢性T. gondii感染的免疫控制取决于保护性CD8+ T细胞反应的发展。目前，我们对寄生虫和宿主机制的了解有限，这些知识决定了保护性CD8+ T细胞反应的启动。 T. gondii感染的宿主细胞，特别是感染的抗原呈现细胞类型，例如树突状细胞和巨噬细胞，在启动保护性CD8+ T细胞反应中起着主要作用。新兴的证据还指出，寄生虫分泌的蛋白是T. gondii的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假设寄生虫分泌的蛋白质在控制CD8+ T细胞反应的启动中通过感染的抗原呈递细胞起着核心作用。因此，我们建议研究来自毒性I型菌株（AIM 1）和慢性II型菌株（AIM 2）在体外启动CD8+ T细胞中的特定寄生虫分泌蛋白的作用。我们的模型预测，寄生虫分泌的蛋白会操纵感染细胞素CD8+ T细胞反应的能力。为了检验这一假设，我们将测量缺乏特定分泌的CD8+ T细胞的I型或II型突变体感染的宿主细胞的能力。该创新R21提案的目标3将进一步研究AIM 1中鉴定出的特定分泌蛋白的作用，AIM 2在离体测定中，以进一步了解寄生虫分泌蛋白在T. gondii感染期间调节天然CD8+ T细胞种群启动的机制。总的来说，这些目标将在功能上确定寄生虫分泌的蛋白质，以确定保护性宿主反应，控制或控制感染的控制，因此将确定新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，宿主细胞操纵和宿主反应的基本方面。