Elucidating the role of carbon metabolism genes chiA and yjiY in Salmonella pathogenesis.

Abstract

Salmonella is a foodborne pathogen that causes debilitating enteric diseases in a wide range of hosts. While Salmonella Typhimurium causes self-limiting gastroenteritis in human beings, Salmonella Typhi causes typhoid fever that has plagued through history and continues to be a major threat to public health even after tremendous advancements in the field of medicine. A related but evolutionarily distinct serovar Salmonella Paratyphi serotype A is the etiological agent of a similar enteric fever known as paratyphoid. While Salmonella Typhimurium can cause gastroenteritis like disease in a broad range of hosts, what makes Salmonella Typhi and S. Paratyphi strict human pathogens, is not clearly understood. When contaminated food is ingested, Salmonella passes through the acidic gastric environment and reaches the intestine. The pathogen crosses intestinal mucus layer and invades enterocytes by engaging SPI1 encoded T3SS mediated effectors that triggers membrane ruffling. Some bacteria are taken up directly by the specialized microfold or M cells present on the Peyer’s patches. This induces IL8 production by the epithelial cells, leading to infiltration of the perimorphonuclear cells and localized inflammation. Once the bacteria transcytose through the epithelial cells, tissue resident macrophages and dendritic cells engulf the bacteria by macropinocytosis. This step marks the beginning of systemic dissemination of the pathogen in the host. Bacterial infections accounts for approximately 80-90% of all food-borne disease outbreaks every year, with Escherichia coli, Salmonella enterica and Listeria monocytogenes infections being the primary ones. Thus studying host-pathogen interaction is critical in understanding the interaction between a pathogenic microorganism and its broad host range. Although commensals and innate immune system work together to keep pathogens at bay, rapid adaptation of the pathogens to evade host’s immune system remains to be a continuous concern. Along with conventional virulence factors such as fimbriae, flagella, ion transporters, pathogenicity islands, Salmonella and many other pathogens code for metabolism-related genes that help them survive better in their respective hosts. Since carbon metabolism is central to all living beings, we hypothesised that alteration of carbon metabolism could affect survival and virulence of a pathogen. Therefore, we have studied two such carbon metabolising genes. The second and third chapter deal with understanding the crosstalk between virulence and chitin degrading enzyme Chitinase A (chiA) in the pathogenesis of Salmonella Typhimurium and Salmonella Typhi, respectively. The fourth chapter explores the molecular mechanism of biofilm inhibition by secretory metabolome of a carbon starvation inducible peptide transporter YjiY mutant.