Drosophila melanogaster as a model host for Vibrio cholerae

黑腹果蝇作为霍乱弧菌的模型宿主

• 批准号: 7257547
• 负责人: PAULA I WATNICK
• 金额: $ 42.25万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-06-01 至 2011-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7257547
• 关键词: Adenylate Cyclase; Apoptosis; Apoptotic; Arthropod Vectors; Arthropods; Attenuated; Attenuated Live Virus Vaccine; Bacteria; Bacterial Toxins; Biology; Calcium-Activated Potassium Channel; Cessation of life; Cholera; Cholera Toxin; Cholera Vaccine; Development; Diarrhea; Disease; Drosophila genus; Drosophila melanogaster; Emerging Communicable Diseases; Environment; Enzymes; Epidemic; Epithelial Cells; Epithelium; Feces; Future; Gastrointestinal tract structure; Genes; Genetic Screening; Genetic Transcription; Genetic screening method; Genome; Glycosphingolipids; Homologous Gene; Human; Immune; Immune response; Immune system; Infection; Inflammatory; Ingestion; Insecta; Integration Host Factors; Intestines; Life; Light; Mammalian Cell; Mediating; Modeling; Morbidity - disease rate; Natural Immunity; Numbers; Organism; Peptide Synthesis; Personal Satisfaction; Phagocytosis; Phenotype; Phosphorus; Play; Potassium Channel; Predisposition; Production; Proteins; Reactive Oxygen Species; Reporting; Research Personnel; Resistance; Role; Signal Pathway; Study models; Testing; Vibrio cholerae; Virulence Factors; Virus Diseases; Work; antimicrobial peptide; base; biodefense; caspase-8; fly; halophilic bacteria; improved; mutant; novel therapeutics; pathogen; programs; research study; response; vector

DESCRIPTION (provided by applicant): Vibrio cholerae, a gram-negative halophilic bacterium found in aquatic environments is the causative agent of the epidemic and deadly diarrheal disease cholera. We have previously shown that ingestion of pathogenic strains of V. cholerae by Drosophila melanogaster results in lethal infection. This infection is dependent on cholera toxin expression by the bacterium as well as on the presence of wild-type levels of adenylyl cyclase, Gsa, and Ca2+-activated K+ channels in the fly. These findings support the conclusion that cholera toxin is the primary virulence factor in both human and Drosophila infection and acts by a similar mechanism in both of these organisms. Based on these results, we hypothesize that the fly may be a useful and practical model host in which to identify host factors that impact the course of V. cholerae infection. To this end, we have initiated a forward genetic screen to identify Drosophila mutants whose susceptibility ty. These experiments will lay the ground work for future studies using the fly as a model to identify novel therapeutics for cholera, modulators of the immune response to V. cholerae, and factors that influence the susceptibility of the mammalian host to V. cholerae infection. We propose to complete the following specific aims: Specific Aim 1: Completion of a genetic screen to identify host proteins that impact the susceptibility of Drosophila melanogaster to V. cholerae infection. Specific Aim 2: To establish intestinal apoptosis as a factor in the susceptibility of Drosophila to V. cholerae infection and to identify the Drosophila signaling pathways that modulate intestinal apoptosis. Specific Aim 3: To identify Vibrio cholerae factors those are responsible for stimulation of the apoptotic response.

描述（由申请人提供）：霍乱弧菌是一种在水生环境中发现的革兰氏阴性嗜盐细菌，是流行性和致命性霍乱的病原体。我们先前已经证明，果蝇摄入霍乱弧菌的致病菌株会导致致死性感染。这种感染是依赖于霍乱毒素表达的细菌，以及在野生型水平的腺苷酸环化酶，GSA，和Ca2+激活的K+通道的苍蝇。这些发现支持了这样的结论，即霍乱毒素是人类和果蝇感染的主要毒力因子，并且在这两种生物体中通过相似的机制起作用。基于这些结果，我们假设苍蝇可能是一个有用的和实用的模式主机，以确定宿主因素，影响霍乱弧菌感染的过程中。为此，我们已经开始了一个向前的遗传筛选，以确定果蝇突变体的易感性。这些实验将为未来的研究奠定基础，使用苍蝇作为模型，以确定霍乱的新疗法，对霍乱弧菌免疫反应的调节剂，以及影响哺乳动物宿主对霍乱弧菌感染易感性的因素。我们建议完成以下具体目标： 具体目标1：完成遗传筛选，以识别影响黑腹果蝇对霍乱弧菌感染易感性的宿主蛋白质。 具体目标二：确定肠道细胞凋亡是果蝇对霍乱弧菌感染易感性的一个因素，并确定调节肠道细胞凋亡的果蝇信号通路。 具体目标3：鉴定负责刺激凋亡反应的霍乱弧菌因子。