A host protein network necessary for parasite cytolysis

描述（由申请人提供）：从病毒到真核生物的细胞内病原体在世界范围内引起重大疾病。这些病原体生命周期中的一个重要过程是在细胞内复制后有效地退出宿主细胞的能力。与众所周知的出芽或凋亡等退出策略相反，本提案将重点关注细胞内寄生虫如何利用细胞溶解作为退出策略，其分子细节尚不清楚。我们之前的研究发现，这两种顶复合体都使用钙调节的宿主蛋白酶钙蛋白酶来退出宿主细胞。我们假设胞内溶细胞寄生虫利用一套复杂的钙调节宿主蛋白

DESCRIPTION (provided by applicant): Intracellular pathogens from viruses to eukaryotes cause significant disease worldwide. An essential process in the life cycle of these pathogens is the ability to efficiently exit from host cells after intracelular replication. As opposed to the wll-characterized strategies of exit such as budding or apoptosis, this proposal will focus on how intracellular parasites utilize cytolysis as an exit strategy, the molecular details of which are poorly understood. Our prior studies led to the discovery that these two apicomplexans both use the calcium regulated host protease calpain in order to exit from their host cells. We hypothesize that intracellular cytolytic parasites utilize a complex set of calcium regulated host proteins for efficient egress. We will test this hypothesis using two Apicomplexan organisms, P. falciparum and T. gondii. Plasmodium sp., which causes malaria, is responsible for worldwide morbidity and mortality for which new therapies are urgently needed. Toxoplasma infection poses serious problems during congenital infection of humans, agriculturally important animals, and in immunocompromised adults. Plasmodium and Toxoplasma are obligate intracellular pathogens with similar virulent lytic cycles. During these lytic cycles parasites invade host cells and establish a specialized compartment within the host cell called the parasitophorous vacuole, within which they complete their entire intracellular cycle. After replication, daughter parasite cells must exit their host cell via lysis of both the vacuolar membrane and the host plasma membrane. We herein propose to integrate cell biological, molecular genetics, and pharmacological approaches to elucidate the activation, function, and significance of this host network for parasite cytolysis.