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

这项建议中的实验旨在确定导致沙门氏菌生物膜发育的营养信号，探索生物膜在宿主内部形成的可能性，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明显的生存优势，我们想要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。导致胃肠炎的沙门氏菌菌株每年在加拿大造成数千起食源性感染，被认为在宿主和环境之间来回循环。相比之下，导致系统性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，而不需要延长环境阶段。众所周知，胃肠炎菌株主要是生物被膜阳性，而系统性菌株是生物被膜阴性；通过比较这些菌株的表型和基因型别，我们将识别导致生物被膜形成的获得或丧失的基因组特征。最后，作为之前发现号资助研究的延伸，我们将致力于确定功能未知的生物膜相关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适应的一部分而被激活的基因。这些基因的协调调控被预测为进化适应的一部分，使沙门氏菌能够在宿主和非宿主环境之间顺利过渡。我提议的研究包括有针对性的方法检查特定的基因，以及涉及下一代测序的全基因组分析。 拟议的研究途径的交叉将使人们更好地了解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。我的长期研究目标是制定战略，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.