In causing disease, bacterial pathogens establish an infectious niche and generate damage within the mammalian host. We investigate three bacterial pathogens to understand the host-microbe interactions that promote colonization and disease, and then, during resolution of infection, mediate microbial clearance. Enterohemorrhagic Escherichia coli (EHEC) O157:H7 is a food-borne intestinal pathogen that that colonizes the intestinal epithelium and produces shiga toxin, a which is responsible for cause systemic disease, including renal failure. We developed a murine model of EHEC infection to understand mechanisms of colonization and disease, as well as to develop therapeutic or preventative interventions. Streptococcus pneumoniae, an important cause of lung infection, causes damage largely by inducing a vigorous host inflammatory response, and we are investigating how the pathogen is recognized by the host with a goal of modulating the acute immune response to mitigate disease. Finally, the Lyme disease spirochete Borrelia burgdorferi, each can establish a localized infection but are also capable of spreading throughout the host. We investigate spirochete-host interactions that promote bloodstream survival and tissue invasion.