Dense granule protein virulence factors in Toxoplasma gondii infection

描述：弓形虫是HIV/AIDS患者的一种重要的机会性感染。艾滋病免疫抑制期间重新激活的感染导致难以治疗和危及生命的急性弓形体脑炎。目前还没有可以根除潜伏的组织包囊或预防艾滋病毒/艾滋病患者再次感染风险的治疗方法。必须确定能够有效预防和治疗艾滋病毒/艾滋病患者反复感染的新战略和新目标。弓形虫菌株类型依赖的毒力机制由棒状蛋白介导，中和宿主先天免疫摧毁细胞内寄生虫的关键机制。阐明不依赖于寄生虫菌株类型的毒力因子可以为不同寄生虫菌株引起的急性和慢性感染建立新的药物靶点。致密颗粒GRA12基因在不同类型弓形虫之间高度保守。我们假设GRA12基因同源基因是毒力、阶段分化、包囊生物学和传染性的中央调节因子。在特定的im1中，我们将使用有针对性的遗传方法来确定致密颗粒GRA12基因同源基因是否为菌株类型无关的毒力因子。我们还将确定GRA12基因同源序列是否影响或与杆状病毒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实验来研究GRA12基因对囊肿期生物学的作用，以探讨它们在囊肿期分化、囊肿期和囊肿期中的功能。 发展，和慢性感染。这一目标还将检验GRA12基因副序列在维持慢性感染期间的囊负荷方面发挥重要作用的假设。总而言之， 这些目的是为了探索新发现的GRA12基因家族蛋白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GRA12基因平行序列作为新的药物靶点，以拦截急性和慢性感染阶段。这项研究项目探索了一种新颖的生物学，它对成功的细胞内寄生、阶段分化和传播具有重要意义。因此，这个R21项目具有极高的创新性，以及在该领域产生持续、强大影响的潜力。

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.