Bacteria are capable of establishing a wide variety of interactive relationships with eukaryotic hosts that may be symbiotic, commensal or parasitic. In humans, such parasitic relationships result in both overt and covert disease. One site where prokaryotic- eukaryotic interactions are particularly diverse and clinically relevant is in the mammalian intestinal tract, where a vastly complex ecosystem of bacteria interfaces with an immense epithelial surface. It has become apparent that both host and microbe influence each other's physiological function to arrange a generally, though not absolutely, mutually beneficial coexistence. Clinical syndromes such as idiopathic inflammatory bowel disease may result when this mutual tolerance breaks down. Furthermore, some bacteria have evolved lifestyles that directly or indirectly elicit host responses characteristic of tissue injury, thus these organisms are generally considered pathogens. A classic example is the common Gram negative enteropathogen Salmonella. These organisms are causal of a variety of clinical syndromes, including inflammatory diarrhea, systemic typhoid fever, reactive (non-infectious) arthritis and potentially, other previously unrecognized, medically important manifestations. Recent technical developments have permitted large-scale, parallel analysis of gene expression, or """"""""expression profiling"""""""". These methods allow genome-wide analysis of regulatory programs elicited by given stimuli. In this proposal we will employ the approach of infection/colonization with bacteria. For most of our proposed studies, we will utilize Salmonella typhimurium, for which we have characterized a spectrum of genetic and environmental variables that affect virulence. We will analyze other strains of Salmonella, both pathogenic and non-pathogenic, with the overall goal of defining a host """"""""expression profile"""""""" of bacterial pathogenesis that will be of great utility in the study of host interactions with other pathogens. More significantly, these data will be invaluable in the recognition of these signatures in human diseases potentially associated with infection by known and unknown organisms.
