Understanding the role of biofilm formation in the lifecycle of pathogenic Salmonella strains

本实验旨在识别导致沙门氏菌生物膜发育的营养信号，探索生物膜在宿主体内形成的可能性，并更好地定义导致其形成的复杂调控网络。细胞聚集成致密的生物膜在应激条件下提供了独特的生存优势，我们想研究这如何有助于沙门氏菌和相关肠道病原体的致病成功。导致肠胃炎的沙门氏菌菌株每年在加拿大造成数千例食源性感染，并且被认为在宿主和环境之间来回循环。相比之下，引起全身感染的沙门氏菌菌株，如伤寒，被认为是直接在人与人之间传播的，没有长时间的环境阶段。众所周知，胃肠炎菌株主要是生物膜阳性，全身性菌株是生物膜阴性；通过比较这些菌株的表型和基因型，我们将确定负责生物膜形成的获得或损失的基因组特征。最后，作为先前“发现”基金资助研究的延伸，我们将努力确定与生物膜相关的未知功能基因在沙门氏菌持续存在中的作用，以及作为细胞引起感染所需的适应的一部分而被激活的基因。据预测，这些基因的协调调节是进化适应的一部分，使沙门氏菌能够在宿主和非宿主环境之间顺利过渡。我建议的研究包括检测特定基因的针对性方法，以及涉及下一代测序的全基因组分析。******所提出的研究途径的交叉将导致对这些重要的人类病原体的生命周期和生物膜形成的潜在作用有更深入的了解。我的长期研究目标是制定策略，以减少每年在世界各地造成的数百万沙门氏菌感染。

The experiments in this proposal are designed to identify the nutritional signals that lead to Salmonella biofilm development, to explore the possibility that biofilms can form inside the host, and to better define the complex regulatory network that leads to their formation. The aggregation of cells into dense biofilms provides a distinct survival advantage under stressful conditions and we want to investigate how this contributes to the pathogenic success of Salmonella and related enteric pathogens. The Salmonella strains that cause gastroenteritis are responsible for thousands of food-borne infections each year in Canada and are thought to cycle back and forth between hosts and the environment. In contrast, Salmonella strains that cause systemic infections, such as typhoid fever, are thought to be transmitted directly from person to person, without a prolonged environmental phase. It is known that gastroenteritis strains are predominantly biofilm-positive and systemic strains are biofilm-negative; by comparing the phenotypes and genotypes of these groups of strains we will identify genomic signatures that are responsible for gain or loss of biofilm formation. Finally, as an extension of previous Discovery grant-funded research, we will work to identify roles of biofilm-related genes of unknown function in the persistence of Salmonella as well as genes that are activated as part of the adaptations required for cells to cause infections. The coordinated regulation of these genes is predicted to be part of the evolutionary adaptations that allow Salmonella to transition smoothly between host and non-host environments. My proposed research consists of targeted approaches examining specific genes, coupled with genome-wide analyses that involve next-generation sequencing.******The intersection of the proposed avenues of research will lead to a greater understanding of the lifecycle of these important human pathogens and the potential roles of biofilm formation. My long-term research goal is to develop strategies to reduce the millions of Salmonella infections that are caused around the world each year.