Investigating the Role of Cellular Signaling in Liver-Stage Malaria Infection

研究细胞信号传导在肝期疟疾感染中的作用

• 批准号: 8001602
• 负责人: Alexis Kaushansky
• 金额: $ 4.96万
• 依托单位: SEATTLE BIOMEDICAL RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-06-01 至 2013-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8001602
• 关键词: Anopheles Genus; Apoptosis; Apoptotic; Attenuated; Attenuated Live Virus Vaccine; Biological Assay; Bite; Blood; Candidate Disease Gene; Cell Culture Techniques; Cells; Culicidae; Development; Disease; Female; Health; Hepatocyte; Home environment; Human; Immune system; Immunity; Immunization; Induction of Apoptosis; Infection; Inhibition of Apoptosis; Intervention; Lead; Liver; Malaria; Modeling; Monitor; Mus; Parasites; Phenotype; Proteins; Public Health; Role; Signal Transduction; Signaling Protein; Staging; Sterility; Stimulus; Vaccines; prevent; public health relevance; research study; response

DESCRIPTION (provided by applicant): Malaria presents a severe health burden, particularly in the developing world yet no vaccine is currently available. The parasites enter the human host through the bite of the female Anopheles mosquito and first infect liver hepatocytes, before moving to the blood infection that causes all disease. During liver stage development, parasites protect their home in the host hepatocyte by preventing programmed cell death (apoptosis) of the infected cell. Genetically attenuated parasite (GAP) strains that induce sterile immunity in mice have been developed, and it was shown for one of these strains that it cannot control host cell apoptosis. The mechanism of the inhibition of apoptosis by wildtype parasites, however, has not been elucidated. I will first fully delineate the apoptotic phenotype of hepatocytes infected with wildtype parasites and GAPs using a variety of phenotypic assays. Next, I plan to monitor a number of candidate signaling proteins in hepatocytes in response to both wildtype and GAP infections. This will allow us to identify candidate genes that are differentially activated in response to pro-apoptotic attenuated parasites and anti-apoptotic wildtype parasites. Finally, I propose to further investigate candidate genes that are differentially regulated using a cell culture model, as well as immunization and challenge experiments in mice. This study will lead to the discovery of hepatocyte proteins critical to modulating the inhibition of apoptosis by wildtype parasites. Since infected apoptotic cells are a better stimulus for the immune system than surviving cells, inhibiting these host proteins may cause the induction of apoptosis by wildtype parasites and might also enhance immunity induced by live-attenuated vaccines. Altering the hepatocyte response to infection could convert a wildtype, disease promoting parasite into one that promotes protective immunity and might thus inform new intervention strategies at the early stage of malaria infection. PUBLIC HEALTH RELEVANCE: Malaria presents a major public health burden, particularly in the developing world. The liver stage of malaria is an attractive target for intervention since live-attenuated vaccines that arrest at this stage prevent further infection. This application seeks to investigate the mechanism and role of host cell programmed cell death in wildtype infection and infection with live-attenuated vaccine strains.

描述（由申请人提供）：疟疾造成严重的健康负担，特别是在发展中国家，但目前尚无疫苗可用。寄生虫通过雌性按蚊叮咬进入人类宿主，首先感染肝脏肝细胞，然后转移到导致所有疾病的血液感染。在肝脏阶段发育期间，寄生虫通过防止受感染细胞的程序性细胞死亡（细胞凋亡）来保护其在宿主肝细胞中的家园。已经开发出诱导小鼠不育免疫的遗传减毒寄生虫（GAP）菌株，其中一种菌株被证明不能控制宿主细胞凋亡。然而，野生型寄生虫抑制细胞凋亡的机制尚未阐明。我将首先使用各种表型测定来全面描述感染野生型寄生虫和 GAP 的肝细胞的凋亡表型。接下来，我计划监测肝细胞中针对野生型和 GAP 感染的一些候选信号蛋白。这将使我们能够识别针对促凋亡减毒寄生虫和抗凋亡野生型寄生虫而差异激活的候选基因。最后，我建议进一步研究使用细胞培养模型差异调节的候选基因，以及小鼠的免疫和攻击实验。这项研究将发现对调节野生型寄生虫抑制细胞凋亡至关重要的肝细胞蛋白。由于受感染的凋亡细胞比存活细胞更能刺激免疫系统，因此抑制这些宿主蛋白可能会诱导野生型寄生虫诱导细胞凋亡，也可能增强减毒活疫苗诱导的免疫力。改变肝细胞对感染的反应可以将一种野生型、促进疾病的寄生虫转变为一种促进保护性免疫的寄生虫，从而可能为疟疾感染早期阶段的新干预策略提供信息。 公共卫生相关性：疟疾是一项重大的公共卫生负担，特别是在发展中国家。疟疾的肝脏阶段是一个有吸引力的干预目标，因为在这个阶段停止的减毒活疫苗可以防止进一步感染。本申请旨在研究宿主细胞程序性细胞死亡在野生型感染和减毒活疫苗株感染中的机制和作用。