The initial steps of Salmonella pathogenesis involve adhesion and invasion of host epithelial cells. While well-studied for S. Typhimurium, the factors contributing to this process in other, host-adapted serovars remains unexplored. Here, we screened clinical isolates of serovars Gallinarum, Dublin, Choleraesuis, Typhimurium and Enteritidis for adhesion and invasion of intestinal epithelial cell lines of human, porcine, and chicken origins. 30 isolates with altered infectivity were used for genomic analyses and 14 genes and novel mutations associated with high or low infectivity were identified. The functions of candidate genes included virulence gene expression regulation, cell wall or membrane synthesis and components. The role of several of these genes in Salmonella adhesion and invasion to cells has not previously been investigated. The genes dksA (stringent response regulator) and sanA (vancomycin high-temperature exclusion protein) were selected for further analyses, and we confirmed their roles in host cell adhesion and invasion. Furthermore, transcriptomic analyses were performed for S. Enteritidis and S. Typhimurium, with two highly infective and two marginally infective isolates for each serovar. Expression profiles for the isolates with altered infection phenotypes revealed the importance of T3SS expression levels in the determination of isolate's infection phenotype. Taken together, these data indicate a new role in cell host infection for genes or gene variants previously not associated with adhesion and invasion to the epithelial cells. Importance Salmonella is a foodborne pathogen affecting over 200 million people and resulting in over 200,000 fatal cases per year. Adhesion to and invasion of Salmonella into intestinal epithelial cells is one of the first and key steps in the pathogenesis of salmonelosis. Still, around 35-40% of bacterial genes have no experimentally validated function and their contribution to the bacterial virulence, including adhesion and invasion, remains largely unknown. Therefore the significance of this study is in the identification of new genes or gene allelic variants previously not associated with adhesion and invasion. It is well established that blocking adhesion and/or invasion would stop or hamper bacterial infection, therefore the new findings from this study could be used in future developments of anti-Salmonella therapy targeting genes involved in these key processes. Such treatment could be a valuable alternative as the numbers of antibiotic-resistant bacteria is growing very rapidly.
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