DIFFERENTIAL EARLY INTERACTIONS BETWEEN SALMONELLA-ENTERICA SEROVAR TYPHI AND 2 OTHER PATHOGENIC SALMONELLA SEROVARS WITH INTESTINAL EPITHELIAL-CELLS

Salmonella enterica serovar Typhi (hereafter referred to as S. typhi) is a host-restricted pathogen that adheres to and invades the distal i leum and subsequently disseminates to cause typhoid fever in humans. H owever, S. typhi appears to be avirulent in small animals. In contrast , other pathogenic salmonellae, such as S. enterica serovars Typhimuri um and Dublin (S. typhimurium and S. dublin, respectively), typically cause localized gastroenteritis in humans hut have been used as models for typhoid fever because these organisms cause a disease in suscepti ble rodents that resembles human typhoid. In vivo, S. typhi has been d emonstrated to attach to and invade murine M cells but is rapidly clea red from the Peyer's patches without destruction of the hi cells. In c ontrast, invasion of M cells by S. typhimurium is accompanied by destr uction of these M cells and subsequently sloughing of the epithelium. These data have furthered our view that the early steps in the pathoge nesis of typhoidal and nontyphoidal Salmonella serovars are distinct, To extend this concept, we have utilized an in vitro model to evaluate three parameters of initial host-pathogen interactions: adherence of three Salmonella serovars to human and murine small intestinal epithel ial cell (IEC) lines, the capacity of these salmonellae to invade IECs , and the ability of the bacteria to induce interleukin-6 (IL-6) in th ese cell lines as a measure of host cell activation and the host acute -phase response, The results demonstrate that S. typhi adheres to and invades human small IECs better than either S. typhimurium or S. dubli n. Interestingly, invA and invE null mutants of S. typhi are able neit her to adhere to nor to invade IECs, unlike S. typhimurium invA anal i nvE mutants, which adhere to bent cannot invade IECs, S. typhi also in duces significantly greater quantities of IL-6 in human small IEC line s than either of the other two Salmonella serovars. These findings sug gest that differential host cytokine responses to bacterial pathogens may play an important role in the pathological sequelae that follow in fection. Importantly, S. typhimurium did Plot induce IL-6 in murine IE Cs. Since S. typhimurium infection in mice is often used as a model of typhoid fever, these findings suggest that, at least in this case, th e mouse model does not reflect the human disease. Taken together, our studies indicate that (i) marked differences occur in the initial step s of S. typhi, S. typhimurium, and S. dublin pathogenesis, and (ii) co nclusions about S. typhi pathogenesis that have been drawn from the mo use model of typhoid fever should be interpreted conservatively.