Intravacuolar network dense granule protein biology in chronic Toxoplasma infection

慢性感染弓形虫通常会重新激活并导致危及生命的弓形虫 患有艾滋病或其他免疫缺陷的脑炎患者。慢性传染性支气管炎的分子基础 弓形虫是一种在中枢神经系统发育并持续存在的组织包囊。淘汰赛 对感染者进行包囊治疗可以防止弓形体脑炎和神经认知功能的恶化。 艾滋病毒阳性的人甚至在艾滋病之前就会发生的功能。然而，目前还没有药物或其他治疗方法。 可以针对慢性弓形虫包囊的药物。目前，在基础生物学知识方面存在不足。 关于控制发展、维持和重新激活的寄生虫和寄主生物学 弓形虫包囊。我们假设与液泡内相关的致密颗粒(GRA)蛋白 网络(IVN)膜系统在操纵宿主CD8+T细胞应答中发挥生物学作用 控制慢性感染，以及作为结构、信号或传感组件的生物学作用 影响包囊的发育、包囊的维持和包囊的复活的膜系统 囊肿症。IVN相关GRA蛋白在慢性感染中具有双重作用的假设得到了我们的支持 初步数据。这个探索性的R21方案将研究IVN GRAs在囊性发育中的作用， 维持和重新激活(目标1)，以及在操纵宿主CD8+T细胞反应中决定 是否维持、清除或重新激活包囊(目标2)。我们预计这些影响较大的研究将 扩展我们对调控包囊发育、维持和发育的生物学基础知识 重新激活，并因此可能建立一个分子基础的干预，可以根除慢性 弓形虫感染。

Chronic infection with Toxoplasma gondii will often reactivate and cause life-threatening Toxoplasmic encephalitis in patients with AIDS or other immune deficiencies. The molecular basis of chronic infection with Toxoplasma gondii is the tissue cyst that develops and persists in the central nervous system. The elimination of cysts in infected individuals would prevent Toxoplasmic encephalitis, as well as deteriorating neurocognitive function that occurs in HIV-positive individuals even prior to AIDS. However, no drug or other therapy exists that can target the chronic Toxoplasma cyst. Currently, there is a deficit in fundamental biological knowledge regarding parasite and host biology that controls the development, maintenance, and reactivation of Toxoplasma cysts. We hypothesize that dense granule (GRA) proteins that associate with the intravacuolar network (IVN) membrane system play biological roles in manipulating the host CD8+ T cell responses that control chronic infection, as well as biological roles as structural, signaling, or sensing components of a membrane system that influences the development of cysts, the maintenance of cysts, and the reactivation of cysts. This hypothesis for a dual role for IVN associated GRA proteins in chronic infection is supported by our preliminary data. This exploratory R21 proposal will investigate the role of IVN GRAs in cyst development, maintenance and reactivation (Aim 1), and in manipulating the host CD8+ T cell responses that determine whether cysts are maintained, cleared, or reactivated (Aim 2). We anticipate these high impact studies will expand our fundamental knowledge of the biology that regulates cyst development, maintenance, and reactivation, and may therefore establish a molecular basis for an intervention that can eradicate chronic Toxoplasma gondii infection.