Role of Salmonella virulence genes in bacterial resistance to antimicrobial peptides and systemic disease

Salmonella enterica serovar Typhimurium (S. typhimurium) causes a variety of diseases in susceptible animals, ranging from self-limiting gastroenteritis to acute bacteremia and widespread bacterial replication in reticulo-endothelial tissues leading to host death. Salmonella spp. harbor a number of virulence factors that allow bacteria to survive and replicate within different host micro-environments. Studies have identified Salmonella-specific virulence factors that promote bacterial adherence to host tissues, breach of epithelial barriers and bacterial replication within phagocytic cells. The macrophage-induced gene mig-14 of Salmonella enterica is required for continued replication of S. typhimurium in systemic tissues of susceptible mice at late stages of acute infection. This suggested that mig-14 could encode a gene product required for systemic phases of salmonellosis, and might participate with other gene products in promoting this phase of disease.; This work characterizes the regulation mig-14, and demonstrates that mig-14 is required for bacterial resistance to antimicrobial peptides. mig-14 is not required for modification of bacterial LPS, one known mechanism of antimicrobial peptide resistance. While mig-14 does not appear necessary for replication in unactivated cells of a macrophage-like cell line, treatment of these cells with IFN-γ and LPS attenuates replication of a mig-14 mutant strain to a greater extent than a wild-type strain.; We further demonstrate that virK, the gene immediately upstream of mig-14, is regulated in a similar manner to mig-14 and also contributes to Salmonella antimicrobial peptide resistance. These observations also hold true for somA, a Salmonella homologue of virK. Deletion of virK reduces bacterial replication at late stages of mouse infection, very similarly to a mig-14 mutant. There was not a significant difference in replication in host tissues between wild-type and somA mutant strains during individual infections; however, during co-infection experiments, both virK and somA mutants were significantly attenuated for replication in systemic tissues relative to the wild-type strain. These observations suggest that the acquisition of mig-14, virK, and somA might be a recent event in the evolution of Salmonella pathogenesis and that these genes may serve to protect Salmonella from host inflammatory responses.