Phages and Genomic Variation in Vibrio Cholerae Evolution

霍乱弧菌进化中的噬菌体和基因组变异

• 批准号: 8369505
• 负责人: John Joseph Mekalanos
• 金额: $ 36.6万
• 依托单位: HARVARD MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-09-01 至 2016-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8369505
• 关键词: Acute; Affect; Africa; Agonist; Animals; Area; Asia; Bacteria; Bacteriophage Typing; Bacteriophages; Bangladesh; Biological; Cells; Cholera; Cholera Toxin; Comparative Genomic Analysis; Complex; Cytotoxin; DNA Restriction-Modification Enzymes; Diarrhea; Disease; Dissociation; Ecology; Elements; Enteral; Enterotoxins; Environment; Enzymes; Epidemic; Essential Genes; Event; Evolution; Eye; Funding; Gene Cluster; Genes; Genome; Genomics; Haiti; Horizontal Gene Transfer; Human; Hybrids; Infection; Inflammatory; Investigation; Lead; Learning; Life; Lipase; Lytic; Maps; Mediating; Microbial Biofilms; Molecular; Pakistan; Pathogenesis; Patients; Peru; Play; Point Mutation; Predatory Behavior; Process; Production; Property; Prophages; Resistance; Role; Sampling; Sequence Analysis; Site; Tail; Techniques; Testing; Time; Toxic effect; Variant; Vibrio; Vibrio cholerae; Virulence; Virulence Factors; Virus; Water; comparative; design; esterase; fitness; genome sequencing; mutant; pandemic disease; pathogen; pressure; research study; transmission process

DESCRIPTION (provided by applicant): Vibrio cholerae is the causative agent of cholera, an acute life-threatening diarrhea disease. Cholera epidemics occur with seasonal regularity in endemic areas, such as the Ganges Delta region of South Asia. Cholera epidemics in 2010 in Africa, Pakistan, and Haiti remind us that further investigation of this disease is warranted. The ability of V. cholerae strains to cause severe enteric infection in humans depends on their virulence gene content. Bacterial viruses infecting Vibrio species (vibriophages/phages) are known to play a critical role in the transmission of the virulence genes among different strains of V. cholerae (e.g., cholera toxin genes via the filamentous phage CTXf). Furthermore, our fieldwork in Bangladesh has provided direct evidence that lytic vibriophages seemly end cholera epidemics through predation and influencing infectivity. The objective of this proposal is to learn how vibriophages drive the emergence of new pathogenic clones of V. cholerae through horizontal gene transfer, predation, and other biological interactions that affect properties such as biofilm formation, infectivity and environmental persistence. We will approach this problem with six specific aims 1) we will attempt to reconstruct the chromosomal arrangement of filamentous prophages found in the 7th pandemic strain, the most successful clone of toxigenic V. cholerae; 2) we will study the formation of hybrid filamentous phages encoding virulence properties and different host range; 3) we will use comparative genome sequence analysis of both phages and V. cholerae isolates to deduce the mechanisms of phage- resistance and displacement phages in Bangladesh aquatic environment; 4) we will utilize biofilm-degrading phages to study the effect of biofilm dissociation on V. cholerae infectivity and persistence in th environment; 5) we will test the ability of phages to mediate transfer of virulence genes or to produce virulence factors such as inflammatory molecules, cytotoxins and enterotoxins; 6) we will construct genetically marked phages suitable for environmental release and accurate subsequent molecular tracking in water and patients. PUBLIC HEALTH RELEVANCE: The proposed project will test the hypothesis that viruses active on the bacterium Vibrio cholerae, play many undefined roles in the ecology of this pathogen including specialized forms of horizontal gene transfer, selection of emergent clones, production of virulence factors, and modulation of infectivity. Information gained from these studies may lead to new effective ways to control cholera.

描述（由申请人提供）：霍乱弧菌是霍乱的病原体，霍乱是一种急性危及生命的腹泻病。霍乱疫情在流行地区（例如南亚恒河三角洲地区）具有季节性规律性。 2010年非洲、巴基斯坦和海地的霍乱疫情提醒我们有必要对这种疾病进行进一步调查。霍乱弧菌菌株引起人类严重肠道感染的能力取决于其毒力基因含量。已知感染弧菌物种的细菌病毒（弧菌噬菌体/噬菌体）在毒力基因在不同菌株之间的传播中发挥着关键作用。 霍乱弧菌（例如，通过丝状噬菌体 CTXf 传播的霍乱毒素基因）。此外，我们在孟加拉国的实地工作提供了直接证据，表明裂解弧菌似乎可以通过捕食和影响传染性来结束霍乱流行。该提案的目的是学习 噬菌体如何通过水平基因转移、捕食和其他影响生物膜形成、感染性和环境持久性等特性的生物相互作用来驱动霍乱弧菌新致病性克隆的出现。我们将通过六个具体目标来解决这个问题：1）我们将尝试重建第七种大流行菌株（产毒霍乱弧菌最成功的克隆）中发现的丝状噬菌体的染色体排列； 2）我们将研究编码毒力特性和不同宿主范围的杂种丝状噬菌体的形成； 3）我们将利用噬菌体和霍乱弧菌分离株的比较基因组序列分析来推断孟加拉国水环境中噬菌体抗性和置换噬菌体的机制； 4）我们将利用生物膜降解噬菌体来研究生物膜解离对霍乱弧菌感染性和环境中持久性的影响； 5）测试噬菌体介导毒力基因转移或产生炎症分子、细胞毒素、肠毒素等毒力因子的能力； 6）我们将构建适合环境释放的基因标记噬菌体，并在水和患者中进行准确的后续分子追踪。 公共健康相关性：拟议项目将检验以下假设：对霍乱弧菌有活性的病毒在该病原体的生态学中发挥许多未定义的作用，包括特殊形式的水平基因转移、新兴克隆的选择、毒力因子的产生和感染性的调节。从这些研究中获得的信息可能会带来控制霍乱的新有效方法。