INOCULUM COMPOSITION AND SALMONELLA PATHOGENICITY ISLAND-1 REGULATE M-CELL INVASION AND EPITHELIAL DESTRUCTION BY SALMONELLA-TYPHIMURIUM

In the mouse model of Salmonella typhimurium infection, the specialize d antigen-sampling intestinal M cells are the primary route of Salmone lla invasion during the early stages of infection, Under certain exper imental conditions, M-cell invasion is accompanied by M-cell destructi on and loss of adjacent regions of the follicle-associated epithelium (FAE), although the conditions responsible for expression of the cytot oxic phenotype in a proportion of previous studies have not been defin ed, In the present study, we have demonstrated that the cytotoxic effe ct exerted by wild-type S, typhimurium on mouse Peyer's patch FAE is d ependent on the inoculum composition, We have also demonstrated that t he extent of FAE destruction correlates with the extent of M-cell inva sion, Bacteria inoculated in Luria-Bertani (LB) broth induce extensive FAE loss and exhibit efficient M-cell invasion, whereas bacteria inoc ulated in phosphate-buffered saline fail to induce significant FAE dis ruption and invade M cells at significantly lower levels, Similarly, i noculation in LB significantly enhances invasion of Madin-Darby canine kidney cells by wild-type S, typhimurium. Mutants defective for expre ssion of invA, a component of Salmonella pathogenicity island 1 which is vital for efficient invasion of cultured cells, fail to induce FAE destruction and, when inoculated in LB, are attenuated for M-cell inva sion, Variation in inv gene expression is, therefore, one possible mec hanism by which inoculate composition may regulate the virulence of wi ld-type S, typhimurium. Our findings suggest that the composition of t he gut luminal contents may be critical in determining the outcome of naturally acquired Salmonella infections and that both vaccine formula tion and dietary status of vaccine recipients may significantly affect the efficacy and safety of live Salmonella oral vaccine delivery syst ems.