A host protein network necessary for parasite cytolysis

描述（由申请方提供）：从病毒到真核生物的细胞内病原体在全球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离开宿主细胞的能力。相对于wll所描述的诸如出芽或凋亡的退出策略，该建议将关注细胞内寄生虫如何利用细胞溶解作为退出策略，其分子细节知之甚少。我们先前的研究发现，这两种顶复门都使用钙调节的宿主蛋白酶钙蛋白酶，以退出其宿主细胞。我们假设细胞内溶细胞寄生虫利用一组复杂的钙调节宿主蛋白， 有效的出口我们将使用两种顶复门生物，恶性疟原虫和T。刚地。疟原虫属，引起疟疾的疟疾是世界范围发病率和死亡率的原因，因此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期间造成严重的问题。疟原虫和弓形虫是具有相似毒力溶解循环的专性胞内病原体。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称为寄生虫空泡的专门区室，在其中完成整个细胞内周期。在复制之后，子寄生虫细胞必须通过液泡膜和宿主质膜两者的裂解离开它们的宿主细胞。我们在此建议整合细胞生物学，分子遗传学和药理学方法来阐明寄生虫细胞溶解的宿主网络的激活，功能和意义。 公共卫生相关性：细胞内病原体，如恶性疟原虫，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它们在细胞内复制后离开宿主细胞的能力。我们假设细胞内寄生虫利用宿主蛋白质退出。我们提出的研究结果可能用于开发可能限制耐药性的多种病原体的抗寄生虫药。

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.