Phage biology and diversity in Clostridium difficile

艰难梭菌的噬菌体生物学和多样性

• 批准号: 341450-2010
• 负责人: Fortier, LouisCharles
• 金额: $ 1.97万
• 依托单位: Université de Sherbrooke
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2014
• 资助国家: 加拿大
• 起止时间: 2014-01-01 至 2015-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=549352
• 关键词: Phage; biology; diversity; Clostridium; difficile

Clostridium difficile is currently the most frequent cause of healthcare-associated infectious diarrhea in industrialized countries. Recently, a hypervirulent strain, called NAP1/027, has emerged and has caused several outbreaks since 2001. The epidemiology of C. difficile seems to be evolving rapidly and despite intensive research on this pathogen in recent years, we don't know much about factors that drive C. difficile evolution and the events that might have contributed to the emergence of the NAP1/027 strain. Moreover, recent studies suggest that animals might be natural reservoirs for C. difficile propagation, but the molecular determinants specifying host specificity (e.g. human or animal hosts) are unknown. Prophages, i.e. viruses (or phages) integrated into the chromosome of bacteria, are mobile genetic elements well known to affect their host by multiple ways. However, their role in C. difficile has remained relatively unexplored so far, although several prophages have been isolated. Our long-term objective is thus to assess the role of prophages in C. difficile lifestyle and host specificity, genetic diversity, virulence and evolution. To achieve this goal, we will characterize prophages present in C. difficile isolates from human, animal and environmental origin. Whole genome sequencing and comparative prophage genomics will be performed, which will provide important and novel data regarding genetic diversity and evolution of both prophages and their host, i.e. C. difficile. Phage as well as bacterial gene expression during lysogeny (latent prophage infection) and during active phage replication (lytic cycle) will be studied in the NAP1/027 strain, which will bring important data regarding phage/pathogen/host interactions. In summary, our study will bring highly novel data and new insights on the genetic diversity and contribution of phages in the diversity and rapid evolution of one of the most deadly human pathogens. We also believe that phage/pathogen interaction studies will lead to the discovery of bacterial targets for novel antimicrobial agents.

艰难梭菌目前是工业化国家中与医疗保健相关的感染性腹泻的最常见原因。最近，出现了一种名为NAP 1/027的超强毒株，自2001年以来已引起多次疫情。流行病学研究表明，艰难梭菌似乎正在迅速进化，尽管近年来对这种病原体进行了深入的研究，但我们对驱动C.艰难进化和可能导致NAP 1/027菌株出现的事件。此外，最近的研究表明，动物可能是C。艰难传播，但指定宿主特异性（例如人类或动物宿主）的分子决定因素是未知的。整合到细菌染色体中的前体，即病毒（或前体），是已知通过多种方式影响其宿主的移动的遗传元件。然而，它们在C.艰难梭菌至今仍相对未被研究，尽管已经分离出几种前噬菌体。因此，我们的长期目标是评估前噬菌体在C.艰难的生活方式和宿主特异性，遗传多样性，毒力和进化。为了实现这一目标，我们将描述存在于C.来自人类、动物和环境来源的艰难梭菌分离物。全基因组测序和比较原噬菌体基因组学研究将为原噬菌体及其宿主的遗传多样性和进化提供重要的新数据。很难将在NAP 1/027菌株中研究溶原性（潜伏原噬菌体感染）和活性噬菌体复制（裂解周期）期间的噬菌体和细菌基因表达，这将带来有关噬菌体/病原体/宿主相互作用的重要数据。总之，我们的研究将带来非常新颖的数据和关于遗传多样性的新见解，以及细菌在最致命的人类病原体之一的多样性和快速进化中的贡献。我们还相信，噬菌体/病原体相互作用的研究将导致发现新的抗菌剂的细菌靶标。