Human polymorphonuclear leukocytes (PMNs or neutrophils) are essential to the innate immune response against invading microorganisms. In contrast to the acquired immune response, which is dependent on previous interaction with specific bacteria, the ability of PMNs to kill microorganisms is immediate and non-specific. Inasmuch as PMNs produce highly toxic microbicidal components, moderation of infection-induced inflammation is critical for limiting host tissue destruction. This moderation is especially important given that PMNs are the predominant immune cell in most bacterial infections. A key aspect of our research investigates how PMNs ingest and kill bacteria, and elucidates post-phagocytosis sequelae such as apoptosis, processes crucial for the resolution phase of inflammation. Thus, one of our research objectives is to elucidate molecular processes in human PMNs that facilitate resolution of infection. To that end, we used genomics methodologies to establish a global model of host cell-pathogen interaction that provides fundamental insight into the resolution of infection in humans. A second focus of research in my laboratory investigates how bacterial pathogens such as Staphylococcus aureus and Streptococcus pyogenes (group A Streptococcus or GAS) evade human innate host defense to cause disease. Although most bacteria are killed readily by PMNs, some human pathogens have evolved mechanisms to inhibit phagocytosis and death resulting from exposure to ROS and microbicidal products. For example, strains of S. aureus which produce Panton-Valentine leukocidin cause lethal necrotizing pneumonia in non-immunocomprimised individuals, the molecular basis for which is unknown. We hypothesize staphylococcal pathogenesis includes evasion of PMN killing and undetermined host-susceptibility factors. GAS successfully evades PMN phagocytosis and killing to cause human infections such as pharyngitis and necrotizing fasciitis (flesh-eating syndrome). To date, our studies include identification of genes and proteins used by S. aureus and GAS to evade destruction by human neutrophils, hence contributing to virulence, survival and pathogenesis.