An official website of the United States government.
<p>Salmonella enterica serovar Typhimurium (S. Typhimurium) is a facultative, intracellular pathogen responsible for disease across a broad range of hosts and is a useful model for systemic infection. About 4% of the S. Typhimurium genome is involved in virulence in mice and most of the virulence genes are clustered in regions of the chromosome called "Pathogenicity Islands". Salmonella Pathogenicity Island 1 (SPI-1) contains genes important in the invasion of epithelial cells, while SPI-2 contains genes required for survival and replication in macrophages. It is well known that iron, oxygen, and nitric oxide are also important factors in host-microbe interactions and in oxidative stress. Our long-term goal is to elucidate the regulatory networks in S. Typhimurium that are involved in the coordinated regulation of cellular metabolism, oxidative stress defenses, and pathogenesis in order to advance the development of novel strategies and therapeutics for the treatment and prevention of salmonellosis. We hypothesize that coordinated regulation of cellular redox and iron homeostasis in S. Typhimurium plays an important role in its virulence, metabolism, ability to survive sudden environmental changes encountered in the host, and to cause illness. Our long-term goal is to elucidate the regulatory networks in S. Typhimurium that are involved in the coordinated regulation of cellular metabolism, oxidative stress defenses and pathogenesis in order to advance the development of novel strategies and therapeutics (e.g., vaccines) for the treatment and prevention of salmonellosis. We hypothesize that coordinated regulation of cellular redox and iron homeostasis in S. Typhimurium plays an important role in its metabolism, ability to tolerate sudden environmental changes encountered in the host, expression of virulence genes and ability to cause illness. Our hypothesis is supported by our findings (2) that FNR (the master regulator of anaerobic metabolism) also regulates many of the S. Typhimurium virulence genes (i.e., Salmonella pathogenicity island-1, SPI-1, and the virulence operon, srfAB). Furthermore, an FNR mutant was attenuated, both in vivo and ex vivo. Based on these findings and on our previous experience in microbial biology and oxidative stress, we plan to study the combined global effects of the redox and iron regulators on cellular metabolism and pathogenesis in Salmonella. </p>
<p>NON-TECHNICAL SUMMARY: Understanding the basic physiological properties of Salmonella in terms of its metabolism and how and when the organism expresses its virulent traits, that cause sickness in humans and farm animals, is essential for developing vaccines and other methods to reduce the Salmonella load in the food supply and prevent Salmonellosis in humans. The proposed studies are based on the fact that the gut of the animal host is anaerobic (i.e., has low oxygen concentration) while the food product is aerobic. Clearly the Salmonella cells have to switch their metabolic activities to match the environment they encounter during their life cycle between the food product and the host gut. There are at least three major global regulators that allow the organism to adjust between the aerobic and the anaerobic environments. We believe that these regulators are also involved in the regulation of virulence. We have already exploited one of these global regulators (i.e., FNR) and developed a US-patented live attenuated vaccine strain. In this proposal, we will expand our current studies to discover new and robust Salmonella Vaccines for farm animals to help reduce the incidences of Salmonellosis in humans. </p>