Molecular Biology and Virulence of CTX Phage

CTX 噬菌体的分子生物学和毒力

• 批准号: 8984265
• 负责人: Matthew K WALDOR
• 金额: $ 41.82万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-01-01 至 2017-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8984265
• 关键词: Address; Animal Model; Antibiotic Resistance; Bacteriophages; Biology; Cholera; Communicable Diseases; Communities; Complex; Cyclophosphamide; Disease; Disease Outbreaks; Disease model; Elements; Evolution; Gene Expression; Gene Expression Regulation; Grant; Haiti; Horizontal Disease Transmission; Human; Immune response; Individual; Infant; Infection; Intestines; Investigation; Knowledge; Mobile Genetic Elements; Modeling; Molecular Biology; Oryctolagus cuniculus; Pathogenicity; Pattern; Physiology; Plasmids; Process; Public Health; Research; Vaccines; Vibrio cholerae; Virulence; Work; antimicrobial drug; insight; intestinal homeostasis; mouse model; pathogen; tool; transmission process

Mobile genetic elements have profoundly influenced the evolution of bacterial pathogens. Many determinants of virulence and antibiotic resistance are borne by mobile elements, such as plasmids and bacteriophages, which are capable of horizontal transmission. During the current grant cycle, we explored several fundamental questions regarding the molecular biology of two mobile genetic elements, CTXqj and SXT, which have profoundly influenced the pathogenicity and evolution ofthe cholera pathogen. Vibrio cholerae. Addressing these aims has yielded observations that suggest previously unrecognized mechanisms of bacteriophage gene regulation and new insights regarding the biology and evolution of Integrative Conjugative Elements (ICEs). Furthermore, knowledge gained from these studies proved to be critical for our studies of the origin of the V. cholerae strain that gave rise to the cholera outbreak in Haiti. During this grant cycle, we also expanded the scope of our work to include investigation of new aspects of V. cholerae biology and pathogenicity. In particular, we developed a new infant rabbit model of disease that closely resembles human cholera. We will exploit this model and new high throughput tools we have developed to address three new aims during the MERIT extension period: 1) Assess the spatial and temporal patterns of V. cholerae gene expression during infection; 2) Identify and characterize the determinants of V. cholerae transmission; and 3) Characterize the innate immune response to V. cholerae intestinal colonization. Completion of these studies will provide the most comprehensive knowledge ofthe course of gene expression during infection for any bacterial pathogen. Additionally, it will enhance our understanding of the processes underlying V. cholerae pathogenicity and transmission. Finally, these studies should provide insight into the innate immune response within the intestinal tract, modulation of which has profound ramifications both for normal intestinal homeostasis and for disease. Collectively, these studies will yield valuable new knowledge for the creation of new antimicrobial agents and vaccines.

移动遗传元素对细菌病原体的演变产生了深远的影响。许多 毒力和抗生素耐药性的决定因素由移动元素（例如质粒和）承担 噬菌体，能够水平传播。在当前的赠款周期中，我们探索了 关于两个移动遗传元件的分子生物学的几个基本问​​题，CTXQJ和 SXT，严重影响了霍乱病原体的致病性和进化。弧菌 霍乱。解决这些目标已产生的观察结果，这些观察表明先前未被认可 噬菌体基因调节的机制以及有关生物学和进化的新见解 综合共轭元素（ICE）。此外，从这些研究中获得的知识被证明是 对于我们对霍乱弧菌菌株起源的研究至关重要，这引起了海地的霍乱疫情。 在这个赠款周期中，我们还扩大了工作范围，以包括对V的新方面的调查。 霍乱生物学和致病性。特别是，我们开发了一种新的婴儿兔疾病模型 与人类霍乱非常相似。我们将利用这种模型和新的高通量工具 开发的旨在解决绩效期间的三个新目标：1）评估空间和 感染期间霍乱基因表达的时间模式； 2）识别并表征 V.霍乱传输的决定因素； 3）表征对V.霍乱的先天免疫反应 肠定植。这些研究的完成将提供最全面的知识 任何细菌病原体感染过程中基因表达的过程。此外，它将增强我们的 了解V.霍乱的致病性和传播基础的过程。最后，这些 研究应洞悉肠道内的先天免疫反应，调制 对于正常的肠道稳态和疾病，这具有深远的影响。总的来说，这些 研究将为创建新的抗菌剂和疫苗提供宝贵的新知识。