A host protein network necessary for parasite cytolysis

描述(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导致重大疾病。这些病原体生命周期中的一个基本过程是在细胞内复制后有效地退出宿主细胞的能力。与WLL特有的退出策略(如萌芽或凋亡)不同，该提案将重点放在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。我们先前的研究发现，这两种顶端复合体都使用钙调节的宿主蛋白酶calain来退出宿主细胞。我们假设细胞内的溶细胞性寄生虫利用一组复杂的钙调节宿主蛋白来 有效的出口。我们将使用恶性疟原虫和弓形虫这两种复合体来验证这一假说。引起疟疾的疟原虫是全球发病率和死亡率的罪魁祸首，迫切需要新的治疗方法。弓形虫感染在人类、农业上重要的动物和免疫功能低下的成年人的先天性感染过程中造成严重问题。疟原虫和弓形虫是专性胞内病原体，具有相似的毒力裂解周期。在这些裂解周期中，寄生虫侵入宿主细胞，并在宿主细胞内建立一个专门的隔室，称为寄生液泡，在那里它们完成了整个细胞内周期。复制后，子代寄生虫细胞必须通过空泡膜和宿主质膜的裂解离开宿主细胞。在这里，我们建议结合细胞生物学、分子遗传学和药理学的方法来阐明这个宿主网络对寄生虫细胞溶解的激活、功能和意义。 公共卫生相关性：细胞内病原体，如疟疾寄生虫恶性疟原虫，在世界范围内导致重大疾病。这些病原体在生命周期中的一个重要过程是它们在细胞内复制后退出宿主细胞的能力。我们假设TAT细胞内的寄生虫利用宿主蛋白退出。我们提出的研究结果可能有助于开发针对可能限制耐药性的多种病原体的抗寄生虫药物。

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. PUBLIC HEALTH RELEVANCE: Intracellular pathogens, such as the malaria parasite P. falciparum, cause significant disease worldwide. An essential process in the life cycle of these pathogens is their ability to exit from host cells after intracelular replication. We hypothesize tat intracellular parasites utilize host proteins for exit. The findings from our proposed studies may be of use for the development of antiparasitics for multiple pathogens that may limit resistance.