Dense granule protein virulence factors in Toxoplasma gondii infection

弓形虫感染中的致密颗粒蛋白毒力因子

• 批准号: 8730970
• 负责人: DAVID J BZIK
• 金额: $ 20.25万
• 依托单位: DARTMOUTH COLLEGE
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-08-08 至 2016-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8730970
• 关键词: AIDS/HIV problem; Acquired Immunodeficiency Syndrome; Acute; Address; Biological; Biological Assay; Biology; Brain; Chronic; Chronic Phase; Cyst; Cytoplasmic Granules; Data; Development; Drug Targeting; Encephalitis; Family; Gene Family; Genes; Genetic; Genetic Models; Goals; Guanosine Triphosphate Phosphohydrolases; Human; Immune; Immunity; Immunosuppression; In Vitro; Individual; Infection; Infection prevention; Intercept; Interferons; Intervention; Knock-out; Life; Link; Maintenance; Maps; Mediating; Mus; Natural Immunity; Neospora; Opportunistic Infections; Oral; Orthologous Gene; Parasites; Pathogenesis; Patients; Pharmacotherapy; Play; Proteins; Recurrence; Research Project Grants; Resistance; Risk; Role; Staging; Testing; Tissues; Toxoplasma; Toxoplasma gondii; Toxoplasmosis; Vacuole; Validation; Virulence; Virulence Factors; Virulent; Wild Type Mouse; improved; in vivo; innovation; intracellular parasitism; killings; latent infection; member; novel; paralogous gene; prevent; protein function; public health relevance; rhoptry; transmission process

DESCRIPTION: Toxoplasma gondii is a significant opportunistic infection of HIV/AIDS patients. Reactivated infection during immune suppression in AIDS causes a difficult to treat and life-threatening acute Toxoplasmic encephalitis. No treatment is currently available that can eradicate latent tissue cysts or prevent the risk of reactivated infection in HIV/AIDS patients. Itis essential to identify new strategies and new targets that have the ability to effectively prevent and treat recurrent infections in HIV/AIDS patients. Toxoplasma gondii strain type-dependent virulence mechanisms mediated by rhoptry proteins neutralize key mechanisms of host innate immunity that destroy intracellular parasites. The elucidation of parasite strain type-independent virulence factors could establish new drug targets for both acute and chronic infections caused by different parasite strain types. Dense granule GRA12 gene paralogs are highly conserved between different Toxoplasma strain types. We hypothesize that GRA12 gene paralogs are central regulators of virulence, stage differentiation, cyst biology, and infectivity. In specific im 1 we will use a targeted genetic approach to determine whether dense granule GRA12 gene paralogs are strain type-independent virulence factors. We will also determine whether GRA12 gene paralogs influence, or are associated with, rhoptry protein mediated virulence mechanisms. In specific aim 2 we will examine the role of GRA12 gene paralogs in cyst stage biology using in vitro and in vivo assays to address their functions in stage differentiation, cyst development, and chronic infection. This aim will also examine the hypothesis that GRA12 gene paralogs play an essential role in maintaining cyst burdens during chronic infection. Collectively, these aims explore key virulence and pathogenesis mechanisms of protein members of a newly identified GRA12 gene family. Thus, this high impact project will identify GRA12 gene paralogs as new drug targets to intercept acute and chronic phases of infection. This research project explores biology that is novel and carries fundamental importance for successful intracellular parasitism, stage differentiation, and transmission. Consequently, this R21 project holds extremely high innovation as well as the potential for a sustained, powerful impact in the field.

描述：弓形虫Gondii是艾滋病毒/艾滋病患者的重要机会感染。艾滋病中免疫抑制过程中的重新激活感染会导致难以治疗和威胁生命的急性弓形虫性脑炎。目前尚无可用的治疗方法可以消除潜在的组织囊肿或防止艾滋病毒/艾滋病患者重新激活感染的风险。确定具有有效预防和治疗艾滋病毒/艾滋病患者反复感染的新策略和新目标的新策略至关重要。弓形虫弓形菌株类型依赖性的毒力机制由Rhoptry蛋白介导的中和宿主先天免疫的关键机制破坏细胞内寄生虫。阐明寄生虫菌株类型非依赖性毒力因子可以为由不同的寄生虫菌株类型引起的急性和慢性感染建立新的药物靶标。密集的颗粒Gra12基因旁系同源物在不同的弓形虫菌株类型之间高度保守。我们假设GRA12基因旁系同源物是毒力，分化，囊肿生物学和感染性的核心调节剂。在特定的IM 1中，我们将使用靶向遗传方法来确定密集的颗粒Gra12基因旁系同源物是否是菌株类型非依赖性的毒力因子。我们还将确定GRA12基因旁系同源物是否影响或与Rhoptry蛋白介导的毒力机制有关。在特定目标2中，我们将使用体外和体内测定法中GRA12基因旁系同源物在囊肿生物学中的作用，以解决它们在阶段分化，囊肿中的功能 发育和慢性感染。该目标还将研究以下假设：GRA12基因旁系同源物在慢性感染过程中维持囊肿负担中起着至关重要的作用。共同 这些目的探索了新鉴定的GRA12基因家族的蛋白质成员的关键毒力和发病机制。因此，这个高影响力项目将识别GRA12基因旁系同源物作为拦截感染的急性和慢性阶段的新药物。该研究项目探讨了新颖的生物学，并且对成功的细胞内寄生虫，舞台分化和传播具有根本的重要性。因此，这个R21项目具有极高的创新，并且有可能在该领域产生持续，强大的影响。