Dense granule protein virulence factors in Toxoplasma gondii infection

描述：刚地弓形虫是HIV/AIDS患者重要的机会性感染。艾滋病免疫抑制期间的再激活感染导致难以治疗和危及生命的急性弓形虫脑炎。目前还没有一种治疗方法可以根除潜伏的组织囊肿或预防HIV/AIDS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/艾滋病患者复发性感染的新战略和新目标。由弓形虫蛋白介导的弓形虫菌株类型依赖性毒力机制中和宿主先天免疫破坏细胞内寄生虫的关键机制。阐明与寄生虫毒株类型无关的毒力因子可为不同寄生虫毒株引起的急性和慢性感染建立新的药物靶点。密集颗粒状的GRA12基因同源性在不同弓形虫品系之间高度保守。我们假设GRA12基因是毒力、分期分化、囊肿生物学和感染性的中心调控因子。在具体的研究中，我们将使用靶向遗传方法来确定致密颗粒GRA12基因相似物是否是菌株类型无关的毒力因子。我们还将确定GRA12基因的类似物是否影响或与腺状体蛋白介导的毒力机制有关。在具体的目标2中，我们将通过体外和体内实验来研究GRA12基因在囊肿分期生物学中的作用，以解决它们在囊肿分期分化中的功能

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.