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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Intramural Research (Z01)
Project #
1Z01AI000900-05
Application #
7196690
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
5
Fiscal Year
2005
Total Cost
Indirect Cost
Name
Niaid Extramural Activities
Department
Type
DUNS #
City
State
Country
United States
Zip Code
DeLeo, Frank R; Diep, Binh An; Otto, Michael (2009) Host defense and pathogenesis in Staphylococcus aureus infections. Infect Dis Clin North Am 23:17-34
Kennedy, Adam D; DeLeo, Frank R (2009) Neutrophil apoptosis and the resolution of infection. Immunol Res 43:25-61
Koziel, Joanna; Maciag-Gudowska, Agnieszka; Mikolajczyk, Tomasz et al. (2009) Phagocytosis of Staphylococcus aureus by macrophages exerts cytoprotective effects manifested by the upregulation of antiapoptotic factors. PLoS One 4:e5210
Bubeck Wardenburg, Juliane; Palazzolo-Ballance, Amy M; Otto, Michael et al. (2008) Panton-Valentine leukocidin is not a virulence determinant in murine models of community-associated methicillin-resistant Staphylococcus aureus disease. J Infect Dis 198:1166-70
Palazzolo-Ballance, Amy M; Reniere, Michelle L; Braughton, Kevin R et al. (2008) Neutrophil microbicides induce a pathogen survival response in community-associated methicillin-resistant Staphylococcus aureus. J Immunol 180:500-9
Kennedy, Adam D; Willment, Janet A; Dorward, David W et al. (2007) Dectin-1 promotes fungicidal activity of human neutrophils. Eur J Immunol 37:467-78
Swindle, Emily J; Coleman, John W; DeLeo, Frank R et al. (2007) FcepsilonRI- and Fcgamma receptor-mediated production of reactive oxygen species by mast cells is lipoxygenase- and cyclooxygenase-dependent and NADPH oxidase-independent. J Immunol 179:7059-71
Quinn, Mark T; DeLeo, Frank R; Bokoch, Gary M (2007) Neutrophil methods and protocols. Preface. Methods Mol Biol 412:vii-viii
Burlak, Christopher; Hammer, Carl H; Robinson, Mary-Ann et al. (2007) Global analysis of community-associated methicillin-resistant Staphylococcus aureus exoproteins reveals molecules produced in vitro and during infection. Cell Microbiol 9:1172-90
Kobayashi, Scott D; Sturdevant, Dan E; DeLeo, Frank R (2007) Genome-scale transcript analyses in human neutrophils. Methods Mol Biol 412:441-53

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