Ongoing projects in the laboratory address several questions pertinent to the cell biology of neutrophil-mediated responses during inflammation and host response to infection. We have a longstanding interest in two important aspects of neutrophil biology, namely the NADPH-dependent oxidase and the granule hemeprotein myeloperoxidase (MPO), and are examining various aspects of each during acute inflammation. Ongoing studies include: (1) Definition of the mechanisms of priming of the phagocyte NADPH-dependent oxidase by microbial endotoxins, with detailed analysis of the subcellular localization and phosphorylation state of p47phox and p67phox, organellar redistribution, and the role of prolyl protein isomerases. Studies includes endotoxins from both Francisella and Neisseria; (2) Characterization of regulation and activation of human Duox1 and 2, nonphagocyte members of the the NOX protein family, in the context of airway epithelial cell biology. (3) Analysis of MPO biosynthesis, including identification of specific steps in proteolytic processing, determinants and consequences of heme acquisition, and the physiological role of constitutively secreted proMPO. Integrated into these studies are efforts to identify genotypes underlying inherited MPO deficiency and to define the molecular consequences of the mutations. (4) Elucidation of events occurring in the phagosomes of human neutrophils after ingestion of Staphylococcus aureus, with emphasis both on MPO-dependent biochemical events mediated by the host and on the staphylococcal responses to the antimicrobial toxins generated in phagosomes that culminate in moderate bacterial killing.