Host distribution of intra- and inter-cellular mobile genetic elements in complex microbial communities

复杂微生物群落中细胞内和细胞间移动遗传元件的宿主分布

• 批准号: RGPIN-2022-03455
• 负责人: Ricker, Nicole
• 金额: $ 2.26万
• 依托单位: University of Guelph
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2022
• 资助国家: 加拿大
• 起止时间: 2022-01-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=761928
• 关键词: Host; distribution; intra; inter; cellular

The increasing prevalence of antimicrobial resistance (AMR) in bacteria is a global health crisis. The animal microbiota is a recognized hot spot of horizontal gene transfer (HGT) of AMR genes as it includes both susceptible and antimicrobial resistant commensal bacteria as well as diverse potentially pathogenic species. Understanding the evolution and persistence of mobile AMR determinants within the animal microbiota is imperative to address the dissemination of AMR in a One Health framework, inform policies to effectively mitigate AMR emergence, and evaluate how reducing antimicrobial use will impact persistence of established mobile AMR determinants after selection is removed. Although the use of non-therapeutic antimicrobials has been restricted in agriculture, AMR will continue to be a concern since high levels of resistance have been established over several decades, and therapeutic use of antibiotics will continue to be necessary in order to ensure the health and humane treatment of production animals. Emergence of AMR genes in pathogenic bacteria occurs by two different mechanisms of mobility - movement between genomic locations within a bacterial cell and transfer between two different bacteria. Typically, a previously unknown AMR gene first becomes associated with an intra-cellular mobile genetic element (MGE) that can facilitate movement to different sites within the original bacterial genome. Through these movements, the resistance gene can get mobilized into a larger inter-cellular MGE, such as a plasmid, which can facilitate transfer to a new bacterial host. These events commonly originate in commensal or environmental bacteria and exposure to antimicrobials drives the selection of strains harboring the AMR gene. Continued selection pressure results in dissemination to diverse taxa and favors the emergence of more successful MGE-AMR combinations as evidenced by the increasing prevalence of multi-drug resistant plasmids. My research program aims to identify the host distribution of both intra-cellular and inter-cellular MGEs in complex microbial communities and identify pathways of MGE dissemination that can help predict AMR emergence. I will use culture-enriched metagenomics and proximity ligation sequencing to examine the distribution of MGEs, focusing on swine gut communities due to the known prevalence of AMR and relevance to the pork industry. I will also develop a unified MGE ontology and classification pipeline for metagenomic data and develop methods for testing the mobility of novel MGEs that have yet to be experimentally characterized. I will use these methods to identify and classify MGEs in the swine gut and subsequently to measure changes in the abundance and dissemination of these MGEs in response to antimicrobial use. This research takes a community approach to understanding HGT within the swine microbiota and the evolutionary changes that occur under antibiotic selection in agricultural systems.

细菌中抗菌素耐药性（AMR）的患病率增加是全球健康危机。动物微生物群是AMR基因水平基因转移（HGT）的公认热点，因为它包括易感和抗菌抗性的共生细菌以及潜在的致病物种。必须了解动物微生物群中移动AMR决定素的演变和持久性，必须在一个健康框架中解决AMR的传播，告知政策以有效缓解AMR的出现，并评估在选择后删除抗生素使用的抗生菌使用将如何影响建立的移动AMR确定的持久性。尽管使用非治疗性抗菌药物的使用已受到限制，但由于几十年来已经建立了高水平的抗药性，因此AMR将继续担心，并且将继续使用抗生素的治疗使用，以确保生产动物的健康和人类治疗。致病细菌中AMR基因的出现通过迁移率的两种不同机制 - 细菌细胞内基因组位置之间的运动以及两种不同细菌之间的转移。通常，先前未知的AMR基因首先与细胞内移动遗传元素（MGE）相关联，该基因可以促进向原始细菌基因组中的不同位点运动。通过这些运动，抗性基因可以动员到较大的细胞间MGE，例如质粒，这可以促进转移到新细菌宿主中。这些事件通常起源于共生或环境细菌，暴露于抗菌剂中，可以驱动携带AMR基因的菌株的选择。持续的选择压力导致传播到不同的分类单元，并有利于更成功的MGE-AMR组合的出现，这证明了多药耐药纤溶酶的患病率的提高。我的研究计划旨在确定复杂微生物群落中细胞内和细胞间MGE的宿主分布，并确定可以帮助预测AMR出现的MGE传播途径。我将使用富含文化的宏基因组学和接近结扎测序来检查MGES的分布，这是由于已知的AMR的患病率并与色情行业相关，重点关注猪肠道群落。我还将开发一个统一的MGE本体论和分类管道，以用于元基因组数据，并开发用于测试尚未实验表征的新MGE的迁移率的方法。我将使用这些方法来识别和分类猪肠道中的MGE，然后以响应抗菌剂的使用来测量这些MGE的抽象和传播的变化。这项研究采用了一种社区方法来理解猪菌群中的HGT以及农业系统中抗生素选择下发生的进化变化。