We investigate host-microbe interactions that promote colonization, disease, and,or resolution of infection. We focus on three bacterial pathogens that display distinct infectious strategies. Enterohemorrhagic Escherichia coli O157:H7 is a food-borne intestinal pathogen that that colonizes the intestinal epithelium and produces a potent toxin that is responsible for systemic disease. Streptococcus pneumoniae is an important cause of lung infection that triggers an exuberant acute inflammatory response that promotes tissue damage and disease. The Lyme disease spirochete Borrelia burgdorferi establishes a localized skin infection but is highly adapted to systemic spread. Using diverse experimental systems, including culture-based and animal models, for each pathogen we characterize the interaction of the host and pathogen molecules that are critical for colonization in the specific target tissues, further systemic spread, and promote tissue damage and,or microbial clearance.