Dense granule protein virulence factors in Toxoplasma gondii infection

描述：弓形虫是一种重要的机会性感染的艾滋病毒/艾滋病患者。在艾滋病免疫抑制期间的再活化感染导致难以治疗和危及生命的急性弓形虫脑炎。目前没有治疗方法可以根除潜伏的组织囊肿或预防艾滋病毒/艾滋病患者再次感染的风险。必须确定能够有效预防和治疗艾滋病毒/艾滋病患者复发感染的新战略和新目标。棒状体蛋白介导的弓形虫株型依赖性毒力机制中和了宿主先天免疫的关键机制。阐明寄生虫株型独立的毒力因子可以建立新的药物靶标，用于不同寄生虫株型引起的急性和慢性感染。致密颗粒GRA 12基因同源序列在不同弓形虫株型间高度保守。我们假设GRA 12基因旁系同源物是毒力、阶段分化、孢囊生物学和感染性的中心调节因子。在特定的im 1中，我们将使用靶向遗传方法来确定致密颗粒GRA 12基因旁系同源物是否是菌株类型独立的毒力因子。我们还将确定GRA 12基因旁系同源物是否影响或与棒状蛋白介导的毒力机制相关。在具体的目标2中，我们将使用体外和体内测定来研究GRA 12基因旁系同源物在囊肿阶段生物学中的作用，以解决它们在阶段分化、囊肿形成和发育中的功能。 发展和慢性感染。这一目标还将检验GRA 12基因旁系同源物在慢性感染期间维持囊肿负担方面发挥重要作用的假设。总的来说， 这些目的是探索新鉴定的GRA 12基因家族的蛋白质成员的关键毒力和致病机制。因此，这个高影响力的项目将确定GRA 12基因旁系同源物作为新的药物靶点，以拦截感染的急性和慢性阶段。本研究项目探索生物学是新颖的，并进行成功的细胞内寄生，阶段分化和传输的根本重要性。因此，R21项目具有极高的创新性，并有可能在该领域产生持续、强大的影响。

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.