Regulation of Yersinia pestis flea-borne transmission

鼠疫耶尔森氏菌跳蚤传播的调控

• 批准号: 9176810
• 负责人: Viveka Vadyvaloo
• 金额: $ 45.74万
• 依托单位: WASHINGTON STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-06-15 至 2021-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9176810
• 关键词: 5' Untranslated Regions; Anti-Infective Agents; Antigens; Bacteria; Base Pairing; Bite; Borrelia; Bubonic Plague; Code; Data; Deposition; Dermis; Disease Outbreaks; Ensure; Environment; Fleas; Future; Genes; Genetic; Genetic Translation; Goals; Human; Immune; Immune response; Infection; Knowledge; Life; Link; Mammals; Mediating; Messenger RNA; Microbial Biofilms; Molecular Chaperones; Phagocytes; Phagocytosis; Phase; Phenotype; Physiological; Plague; Pneumonic Plague; Post-Transcriptional Regulation; Primitive foregut structure; Process; Production; Proteins; Public Health; RNA; Regulation; Research; Rickettsia; Role; Site; Staging; Structure; Testing; Tissue-Specific Gene Expression; Toxin; Translations; Untranslated RNA; Virulence; Work; Yersinia; Yersinia pestis; base; disease transmission; fitness; human disease; mRNA Stability; member; mutant; novel; pathogen; residence; tool; transmission process; vector

PROJECT SUMMARY Yersinia pestis, the etiological agent of plague, is mainly transmitted to humans by fleabite. Replication and biofilm formation by Y. pestis in the flea gut are essential steps for flea foregut blockage, a condition which facilitates subsequent transmission of Y. pestis to a mammalian host. Flea-borne transmission thus requires that Y. pestis rapidly adapt to, and overcome, physiological and immunological barriers imposed by two distinctive host environments – first the flea and subsequently the mammal. How flea gut adaptation is regulated to produce a transmissible infection and consequent transmission efficiency represents a significant gap in our knowledge, and understanding this regulation can provide new opportunities to block flea-borne transmission of plague. Toward understanding the regulatory mechanisms necessary for flea-borne transmission of Y. pestis, we have produced evidence that supports testing the hypothesis that Y. pestis biofilm formation in the flea gut is regulated post-transcriptionally by small non-coding RNAs (sRNA). Besides showing that the sRNA chaperone protein, Hfq, is required for biofilm blockage formation and optimal survival and fitness of Y. pestis in the flea gut, we have: (1) identified a unique flea-specific intergenically coded repertoire of sRNAs that are produced by Y. pestis during flea infection; and (2) showed that a Y. pestis mutant of a known sRNA is deficient in its ability to form biofilm blockage in fleas and therefore to transmit the plague agent. Post-transcriptional regulation of sRNAs is facilitated by complementary base pairing to a target mRNA, thereby altering mRNA target stability or translation. Hence, the goals of this study are to: (Aim 1) determine if flea-specific sRNAs regulate the unique Y. pestis biofilm and adaptation to the flea gut; (Aim 2) determine if flea-specific sRNAs prime successful flea-borne transmission of Y. pestis to its mammalian host; and (Aim 3) identify the cognate mRNA targets of sRNAs and characterize the functional interaction between sRNAs and their cognate mRNAs. Cumulatively this data will result in identification of novel transmission and virulence mechanisms in plague transmission that may presumably be conserved in other vector-borne bacterial pathogens.

项目摘要 鼠疫耶尔森氏菌是鼠疫的病原体，主要通过蚤传播给人类。复制和 Y.跳蚤肠道中的鼠疫是跳蚤前肠阻塞的必要步骤， 有助于Y的后续传输。鼠疫杆菌感染哺乳动物宿主因此，跳蚤传播要求 Y.鼠疫菌迅速适应并克服了由两种不同的 宿主环境-首先是跳蚤，然后是哺乳动物。跳蚤肠道的适应是如何被调节以产生 可传播的感染和随之而来的传播效率代表了我们知识上的巨大差距， 了解这一规律可以为阻断鼠疫的蚤媒传播提供新的机会。 为了解蚤媒传播Y.鼠疫，我们有 产生的证据，支持测试的假设，Y。跳蚤肠道中鼠疫生物膜的形成受到调节 小的非编码RNA（sRNA）。除了显示sRNA伴侣蛋白， Hfq是生物膜堵塞形成和Y的最佳存活和适合度所必需的。我们在跳蚤肠道里发现了鼠疫， 已经：（1）确定了一个独特的跳蚤特异性基因间编码的sRNA库，由Y。鼠疫 在蚤感染期间;（2）表明Y.鼠疫菌已知sRNA的突变体缺乏形成 跳蚤中的生物膜堵塞，从而传播鼠疫病原体。sRNA的转录后调控是 通过与靶mRNA的互补碱基配对来促进，从而改变mRNA靶稳定性或翻译。 因此，本研究的目的是：（目的1）确定蚤特异性sRNAs是否调控独特的Y。鼠疫 生物膜和适应跳蚤肠道;（目的2）确定跳蚤特异性sRNAs是否引发成功的跳蚤传播的 传播Y.（目的3）鉴定sRNA的同源mRNA靶标， 表征sRNA及其同源mRNA之间的功能相互作用。这些数据累积起来， 导致鼠疫传播中新的传播和毒力机制的鉴定， 推测在其他媒介传播的细菌病原体中是保守的。