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）：疟疾带来严重的健康负担，尤其是在发展中国家，但目前尚无疫苗。寄生虫通过雌性蚊子蚊子的咬伤进入人类宿主，并首先感染肝肝细胞，然后转化为引起所有疾病的血液感染。在肝阶段发育期间，寄生虫通过防止被感染细胞的程序性细胞死亡（凋亡）来保护其在宿主肝细胞中的家园。已经开发了诱导小鼠无菌免疫的遗传减弱寄生虫（GAP）菌株，并且在这些菌株之一中证明了它无法控制宿主细胞凋亡。但是，尚未阐明野生型寄生虫抑制凋亡的机制。我首先使用多种表型测定法首先充分描述了被野生型寄生虫和间隙感染的肝细胞的凋亡表型。接下来，我计划根据野生型和间隙感染来监测肝细胞中的许多候选信号蛋白。这将使我们能够鉴定候选基因，这些基因因促凋亡的降低寄生虫和抗凋亡野生型寄生虫而被差异化。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，以及小鼠的免疫和挑战实验。这项研究将导致发现肝细胞蛋白对于调节野生型寄生虫对凋亡的抑制至关重要。由于被感染的凋亡细胞比幸存的细胞更好地刺激了免疫系统，因此抑制这些宿主蛋白可能会导致野生型寄生虫诱导凋亡，并且还可能增强由活体受累的疫苗诱导的免疫力。改变肝细胞对感染的反应可能会将野生型，疾病转化为促进寄生虫的疾病，从而促进保护性免疫，因此可能在疟疾感染的早期阶段为新的干预策略提供了信息。 公共卫生相关性：疟疾带来了重大的公共卫生负担，尤其是在发展中国家。疟疾的肝脏阶段是干预的有吸引力的靶标，因为现场停滞的疫苗阻止了进一步的感染。该应用程序旨在研究宿主细胞编程的细胞死亡在野生型感染中的机制和作用，并通过活识别的疫苗菌株感染。