Genetic dissection of the host response to Salmonella Typhimurium infection in Toll-like receptor 4 transgenic mice and recombinant congenic strains

Different individuals react differently to infection with similar pathogens and weakly pathogenic organisms can cause life-threatening infections in some, while highly virulent microbes may go undetected in others. The basis of these differences lies within the genetic makeup of each individual, which determine their response to infection. Unraveling the genetic determinants of susceptibility to infection brings a much clearer understanding of the pathogenesis of diseases and paves the way to potential prophylactic and therapeutic interventions urgently needed in the context of increasing antimicrobial resistance, globalization of infectious diseases, and emerging or re-emerging pathogens.;Here, we present a series of experiments, which contribute to our understanding of the host response to acute Salmonella Typhimurium infection in mice. First, we investigated the impact of Tlr4 expression during Salmonella infection by comparing host responses in mice carrying 1, 2 and 3 copies of Tlr4 on the same genetic background. We show for the first time, in this narrow range of Tlr4 expression, an incremental protective effect against Salmonella due to improved control of bacterial growth and increased expression of important downstream immune genes. Second, using a set of reciprocal A/J and C57BL/6J recombinant congenic strains, we identified five novels QTL influencing the outcome of Salmonella Typhimurium infection in mice. Finally, we present evidence for the genetic basis for one of the newly identified QTL and describe a role for anemia and iron balance in the mouse response to Salmonella..;Salmonella spp are highly successful pathogens that have co-evolved with countless host species. Even today, they continue to threaten public health throughout the world. Their zoonotic nature, their propensity to establish long-term carrier states and the emergence of antimicrobial resistant, highly virulent strains greatly complicate the fight against this pathogen. As for other infectious diseases, the host response to Salmonella is genetically controlled. In order to genetically dissect this response, a mouse model was developed and allowed identification of a few genes having a strong impact on the outcome of Salmonella infection. The mouse response to Salmonella is, however, complex and several additional genetic variants influencing the response to infection remain to be identified.