Molecular Basis of Human Toxoplasmosis

项目摘要/摘要 弓形虫是一种常见的动物寄生虫，也是人类意外感染的常见原因。 急性感染通常由免疫反应控制，但持续的慢性感染会因 对于寄居在组织囊内的半休眠阶段的缓殖体的生存。免疫功能受损 患者，组织囊肿破裂会释放缓殖子，这些缓殖子可以转化为快速复制。 速殖子，由于T细胞免疫力下降而不受限制的过程。重新激活的可能性 给免疫功能低下的患者带来持续的风险，因为免疫系统和 抗生素可以根除慢性感染。因此，仍有必要了解基本情况 研究致病机制，以开发更有效的干预措施。关键的调停人之一 对弓形虫的先天和获得性免疫是产生干扰素，激活细胞来控制 寄生通过各种机制，包括营养耗竭，以寄生液泡为目标 用于破坏或抑制生长。作为世界上最成功的寄生虫之一，T。 弓形虫已经开发出有效的机制来阻断这些免疫控制途径。我们的研究试图定义 弓形虫如何阻断或颠覆干扰素信号以克服宿主防御的分子基础。在 在之前的资助阶段，我们发现了一种分泌型寄生虫蛋白，它可以运输到宿主细胞核，在那里它会与之结合 转录因子STAT1和募集染色质修饰复合体阻断诱导的基因表达 I型(干扰素-β)和II型(干扰素-γ)干扰素。我们之前的研究表明， 寄生虫阻断II型干扰素在急性感染中起主要作用，而它颠覆I型干扰素的能力是 慢性感染时中枢神经系统的关键。我们最近还发现了第二个秘密 效应器，也运输到宿主细胞核，并阻断I型干扰素途径。拟议的研究将 探索这些效应器通过缓殖子抑制干扰素信号的分子机制，从而 确保导致慢性感染的组织囊肿存活。

PROJECT SUMMARY/ABSTRACT Toxoplasma gondii is a common parasite of animals and frequent cause of accidental infection in humans. Acute infections are generally controlled by the immune response, but persistent chronic infection ensues due to survival of semi-dormant stages called bradyzoites that reside within tissue cysts. In immunocompromised patients, rupture of the tissue cysts releases bradyzoites that can convert back to rapidly replicating tachyzoites, a process that goes unrestricted due to decreased T-cell immunity. The potential for reactivation presents a continued risk to immunocompromised patients due to the fact that neither the immune system nor antibiotics can eradicate chronic infections. As such, there is still a need to understand fundamental mechanisms of pathogenicity in order to develop more effective interventions. One of the key mediators of innate and adaptive immunity to T. gondii is the production of interferons that activate cells to control the parasite through a variety of mechanisms including nutrient depletion, targeting the parasitophorous vacuole for destruction, or growth inhibition. As one of the world's most successful parasites, it is not surprising that T. gondii has developed active mechanisms to block these immune control pathways. Our studies seek to define the molecular bases of how T. gondii blocks or subverts interferon signaling to overcome host defenses. In the prior funding period, we identified a secretory parasite protein that traffics to the host nucleus where it binds to the transcription factor STAT1 and recruits a chromatin modifying complex to block gene expression induced by both type I (IFN-β) and type II (IFN-γ) interferons. Our prior studies demonstrate that the ability of the parasite to block type II IFN is primarily important in the acute infection while its ability to subvert type I IFN is key in the central nervous system during chronic infection. We have also recently identified a second secreted effector that also traffics to the host cell nucleus and blocks the type I IFN pathway. The proposed studies will explore the molecular mechanisms by which these effectors inhibit IFN signaling by bradyzoites and thus assure survival of tissue cysts that are responsible for chronic infection.