Pseudomonas aeruginosa is a bacterium that commonly inhabits natural locations such as rivers, lakes, and soil, and may secondarily colonize man-made surfaces like sinks and medical devices. Because of its prevalence, humans are frequently exposed to P. aeruginosa; however, most encounters in nature do not result in disease development. Rather, extremely severe disease, with a mortality of up to 70%, rapidly develops when exposure is coupled with another insult, such as chronic disease like emphysema, hospitalization, or immune suppression. In fact, current research suggests that P. aeruginosa pneumonia among hospitalized patients most frequently originates from previous environmental exposure. The long-term objective of this proposal is to better understand the pathogenesis of P. aeruginosa pneumonia. In particular, the roles of several effector proteins, secreted by a type III secretion system, will be investigated using isogenic bacterial mutants. The work will characterize the relative roles of three effectors proteins in causing acute pulmonary disease, focusing on their functions in the development of pneumonia and in modulating the innate immune response to infection. These experiments will yield a greater understanding of the pathogenesis of acute P. aeruginosa pneumonia and may present potential targets for clinical treatment of these severe infections.