Microbial Adaptation and Evolution Towards Host Specificity

这种细菌，大肠杆菌，是在各种动物和环境的肠道中发现的正常微生物菌群的一部分。已知某些菌株会在动物和人类中引起疾病。一般认为，大肠杆菌可以在不同动物之间传播，因此被认为是一个宿主通才。然而，越来越多的文献表明，这种细菌的菌株在遗传水平上差异很大，这表明一些菌株可能更适合在某些动物宿主或环境中生存，因此，它们进入不同动物种群的能力可能有限（即，它们可能是宿主特异性的）。我实验室最近的研究支持这一观点。本提案中提出的研究试图确定大肠杆菌的新的遗传生物标记物，这些标记物可以确定该有机体可能能够定殖的动物宿主或环境。该研究基于以下假设：大肠杆菌在特定动物宿主或环境肠道内的存活将取决于其感知和响应宿主或环境（即水或废水）肠道生理条件的能力，因此，它是否能够在生态位内竞争其他微生物有限的营养物质/复制位点。由于肠道和环境条件在宿主与宿主之间以及环境与环境之间差异很大，我相信微生物的进化将推动生存策略向宿主专业化方向发展。细菌对肠道/环境中的环境条件“感知和响应”的能力主要编码在“感觉基因组”（即转录组）中，因此对这些控制区的DNA序列进行分析可能会揭示与宿主特异性相关的DNA生物标志物模式。作为一个必然的假设，我相信人类、动物和环境中大肠杆菌的基因间DNA序列“印记”了宿主的特定信息，有助于确定食物和水中大肠杆菌的突发致病性菌株的来源。为了实现这一目标，我的实验室将：a)在5000种动物大肠杆菌分离株中对基因组的目标区域进行大规模测序（我们的团队已经证明携带宿主特异性生物标志物），以及b)使用代表性动物分离株的全基因组测序（辅以人类和动物分离株的公开基因组数据），使用团队成员开发的新型逻辑回归统计工具来识别宿主特异性生物标志物。这项研究对于确定有可能从一种动物宿主传播到另一种动物宿主的致病菌株，或者在出现人畜共患病的情况下（即欧洲的大肠杆菌O104），确定可能与出现有关的动物宿主具有重要意义。这些数据还可用于制定与食品和/或水污染有关的控制措施。

The bacterium, Escherichia coli, is part of the normal microbial flora found in the intestines of a variety of animals and the environment. Certain strains are known to cause disease in both animals and humans. It is generally believed that E. coli can transmit between different animals and is therefore considered to be a host-generalist. However, an increasing body of literature demonstrates that strains of this bacterium are very different at the genetic level, suggesting that some strains may be better adapted to survive within certain animal hosts or environments and, consequently, may have limited ability to cross into different animal populations (i.e., they may be host-specific). Recent research in my laboratory supports this concept. The research presented in this proposal attempts to identify novel genetic biomarkers of E. coli that define which animal host(s) or environments the organism may be capable of colonizing. The research is based on the hypothesis that E. coli’s survival within the gut of a particular animal host or environment will depend on its ability to sense and respond to the physiological gut conditions of that host or environment (i.e., water or wastewater), and consequently, whether it can outcompete other microbes for the limited nutrients/replication sites within the niche. Since gut and environmental conditions vary widely from host-to-host and from environment-to-environment, I believe that microbial evolution will drive survival strategies towards host specialization. The ability of the bacteria to ‘sense-and-respond’ to environmental conditions in the gut/environment is largely encoded in the ‘sensory genome’ (i.e., transcriptome) and consequently an analysis of DNA sequences in these control regions may reveal DNA biomarker patterns that correlate with host-specificity. As a corollary hypothesis I believe that intergenic DNA sequences from E. coli in humans, animals and the environment are 'imprinted' with host specific information, useful for identifying the source of emergent pathogenic strains of E. coli in food and water. To accomplish this, my laboratory will: a) mass sequence targeted areas of the genome (already shown by our group to carry host-specific biomarkers) across 5000 animal E. coli isolates, and b) use whole genome sequencing of representative animal isolates (supplemented with publically available genome data for human and animal isolates) to identify host-specific biomarkers using novel logic regression statistical tools developed by team members. The research is important in identifying disease-causing strains that have the potential to emerge from one animal host into another, or in the case of situations where zoonoses emerge (i.e., E. coli O104 in Europe), what animal reservoirs may have been associated with emergence. The data may also allow for development of control measures related to contamination of food and/or water.