CONTROL OF TOXOPLASMA GONDII GROWTH BY THE HOST CELL TRANSCRIPTION FACTOR HIF1

描述（由申请人提供）：专性细胞内寄生虫弓形虫是艾滋病患者的主要机会性感染。弓形虫还对胎儿和其他免疫功能低下的患者造成毁灭性的疾病。虽然许多工作集中在鉴定和表征弓形虫蛋白质和对这种细胞内病原体的生长和毒力重要的途径，但对哪些宿主细胞途径是寄生虫生长的限速途径知之甚少。识别这些宿主细胞过程是重要的，因为如果我们能够抑制 它们或寄生虫依赖于它们的过程发挥作用，那么我们就可以阻止寄生虫的生长和疾病。调节宿主细胞转录是使宿主细胞环境允许病原体生长的常见机制。在上一个资助期间，我们证明了弓形虫激活一种名为缺氧诱导因子1（HIF-1）的宿主细胞转录因子，并需要HIF-1的生长。HIF-1的激活是通过寄生虫减少PHD 2蛋白的丰度来实现的，PHD 2蛋白是HIF-1的关键负调节因子。PHD 2蛋白的减少是通过寄生虫通过激活素样激酶（ALK）受体家族的信号传导实现的。重要的是，抑制ALK信号传导严重损害寄生虫生长。总之，这些数据表明，ALK/HIF-1信号转导是弓形虫生长的关键宿主细胞决定因素，并代表了微生物病原体颠覆宿主细胞信号转导和转录以建立其复制生态位的新机制。本提案中 我们将确定哪些ALK受体在弓形虫感染过程中起作用，PHD 2蛋白水平如何在寄生虫感染的细胞中控制，并确定寄生虫依赖于宿主ALK/HIF-1信号传导的过程。这些研究有可能为弓形虫与宿主细胞的相互作用提供重要信息。

DESCRIPTION (provided by applicant): The obligate intracellular parasite Toxoplasma gondii is a major opportunistic infection of AIDS patients. Toxoplasma also causes devastating disease to fetuses and other immunocompromised patients. While much work has focused on identifying and characterizing Toxoplasma proteins and pathways important for growth and virulence of this intracellular pathogen, less is known about which host cell pathways are rate- limiting for parasite growth. Identification of these host cell processes is important because if we can inhibit them or the parasite processes dependent on them from functioning then we can block parasite growth and disease. Modulation of host cell transcription is a common mechanism to make the host cell's environment permissive for pathogen growth. During the previous funding period, we demonstrated that Toxoplasma activates a host cell transcription factor named Hypoxia Inducible Factor 1 (HIF-1) and requires HIF-1 for growth. HIF-1 activation is achieved by the parasite decreasing the abundance of the PHD2 protein, which is the key negative regulator of HIF-1. Decreases in PHD2 protein is achieved by the parasite signaling though the Activin Like Kinase (ALK) receptor family. Significantly, inhibition of ALK signaling severely impairs parasite growth. Together these data indicate that ALK/HIF-1 signaling is a key host cell determinant for Toxoplasma gondii growth and represent a novel mechanism by which a microbial pathogen subverts host cell signaling and transcription to establish its replicative niche. In this proposal we will establish which ALK receptors function during Toxoplasma infection, how PHD2 protein levels are controlled in parasite- infected cells, and define the parasite processes dependent on host ALK/HIF-1 signaling. These studies are likely to provide important information regarding the interaction between Toxoplasma and its host cell.