Molecular analysis of Salmonella host specificity

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Molecular analysis of Salmonella host specificity. ***The aim of my research program is to better understand the molecular mechanisms used by bacteria to adhere, invade and survive in host cells. My research is centred mainly on defining the genetic basis of host specificity in related bacterial pathogens. We are using Salmonella enterica as a model bacterium using a serovar that is specific only to one host (S. Typhi), in comparison to a generalist serovar (S. Typhimurium) that can infects many different hosts. We want to understand why S. Typhi is specific to only one host.***Bacterial components at the cell surface, such as fimbrial adhesins, are the first to interact with the surrounding environment. Thus, they are good candidate for being responsible of the host spectrum. During the next grant period, we will focus on the characterization of two adhesion systems, the type IV pilus and the curli fimbriae. It is important to determine the contribution of these adhesion systems in S. Typhi virulence and host specificity. The type IV pilus is unique to S. Typhi and its function is not yet identified. As the type IV pilus of S. Typhi are associated with many functions, such as attachment to host cells, microcolony, biofilm formation, and twitching motility, it will be primordial to determine its role in S. Typhi. The curli fimbriae are the main component of biofilm, a bacterial community associated with adhesion, resistance and persistence. The curli genes are conserved between the serovars, but the regulation seems to be different, as S. Typhi do not produce curli and biofilm under standard laboratory conditions. Interestingly, S. Typhi produces biofilms inside the host, and is then associated with bacterial persistence in the host. Biofilms on gallstones of asymptomatic carrier represent the only known reservoir for this human-specific pathogen.***We will determine the genetic organization, regulatory networks, and evaluate the roles of these two adhesion system in host adaptation of S. Typhi. This project will involve the generation of mutant strains using defined deletion mutations and the use of a broad range of methods including microbial genetics, molecular biology, biochemistry, immunology, cell biology, and microscopy. We will gain a better understanding of the function of two important adhesion systems in the pathogenesis of a bacteria adapted only to human. ***It is anticipated that the research proposed in this application will contribute to our understanding of basic mechanisms of bacterial fitness, adaptation and evolution. This information should also provide important insights regarding the roles of bacterial adhesins. As some of the targeted systems are conserved among other bacteria, this may potentially lead to strategies for prevention and treatment against many bacteria in different environments, both within the host and in environmental settings, such as in water and food sources.********