Grant: CIHR Fellowship

The human intestine harbors an overwhelming number of bacteria. This microbial community (microbiota) confers several advantages to the host, among which is the protection against pathogens. One of the most prevalent intestinal pathogens is Salmonella enterica serovar Typhimurium (St). St enters the human body through the consumption of contaminated food or water. Upon reaching the intestine, St employs sophisticated mechanisms to induce its uptake by intestinal cells. Then, St evades host defenses and proliferates, causing disease. St has to overcome a multitude of challenges imposed by the host and its microbiota in order to cause disease. Therefore, this organism must be able to sense the intestinal environment and respond accordingly in order to adapt. Here, I suggest that St senses chemical signals produced by the host or its microbiota. By doing so, St can determine it has entered the host and activate genes that are important for the development of disease. To investigate this question, I propose to utilize molecular microbiology techniques to identify St genes that are turned on in response to the intestinal microbiota. I also plan to identify the molecules involved and the control systems that turn the target genes on and off. I will then engineer bacterial strains to produce variants that do not carry these genes. These variants will be tested for the capacity to infect mice as an attempt to investigate whether or not these genes are involved in the disease process. For most of these studies, mice will be used as a model for how St might interact with the human gut. Infections caused by St represent a major public health issue. The emergence of antibiotic-resistant strains makes it imperative that new therapeutic approaches be developed. The goal of this project is to identify mechanisms used by St to adapt to conditions encountered in the human body. Such mechanisms represent attractive targets for the development of new antibiotics.