In FY2013, a primary focus of research in my laboratory investigated how bacterial pathogens such as Staphylococcus aureus cause human disease. Although most bacteria are killed readily by PMNs, certain strains of S. aureus have evolved mechanisms to circumvent destruction by neutrophils and thereby cause human infections. Notably, S. aureus is the most frequent etiologic agent causing bloodstream infection, skin and soft tissue infection, and lower respiratory tract infection in much of the world, including the United States. In addition, the pathogen has become increasingly resistant to antibiotics over the past few decades and methicillin-resistant S. aureus (MRSA) is a leading cause of hospital-acquired infections. Thus, treatment options are limited. Hospital-acquired MRSA infections are also typical of individuals with predisposing risk factors. In contrast, community-associated (or acquired) MRSA (CA-MRSA) cause disease in otherwise healthy individuals, and these infections can be severe/fatal. There has been a relatively high number of CA-MRSA infections worldwide, and this includes an ongoing epidemic of CA-MRSA infections in the United States. The molecular basis for the increased incidence and severity of CA-MRSA disease is not known. We hypothesize that the ability of bacteria to cause disease is largely due to pathogen-derived factors that alter normal neutrophil function and individual host susceptibility. Therefore, a better understanding of the bacteria-PMN interface at the cell and molecular levels will provide information critical to our understanding, treatment, and control of disease caused by bacterial pathogens. S. aureus is an ideal model pathogen with which to test our hypothesis because it is an important cause of human disease, it can be multi-drug resistant and thus hard to eradicate, and neutrophils are the first line of defense against S. aureus infections. To date, our studies include identification of genes and proteins used by CA-MRSA to evade destruction by human neutrophils, hence contributing to virulence, survival and pathogenesis.

Project Start
Project End
Budget Start
Budget End
Support Year
6
Fiscal Year
2013
Total Cost
$846,193
Indirect Cost
City
State
Country
Zip Code
Lu, Thea; Porter, Adeline R; Kennedy, Adam D et al. (2014) Phagocytosis and killing of Staphylococcus aureus by human neutrophils. J Innate Immun 6:639-49
Sully, Erin K; Malachowa, Natalia; Elmore, Bradley O et al. (2014) Selective chemical inhibition of agr quorum sensing in Staphylococcus aureus promotes host defense with minimal impact on resistance. PLoS Pathog 10:e1004174
Uhlemann, Anne-Catrin; Otto, Michael; Lowy, Franklin D et al. (2014) Evolution of community- and healthcare-associated methicillin-resistant Staphylococcus aureus. Infect Genet Evol 21:563-74
Greenlee-Wacker, Mallary C; Rigby, Kevin M; Kobayashi, Scott D et al. (2014) Phagocytosis of Staphylococcus aureus by human neutrophils prevents macrophage efferocytosis and induces programmed necrosis. J Immunol 192:4709-17
Cheung, Gordon Y C; Kretschmer, Dorothee; Queck, Shu Y et al. (2014) Insight into structure-function relationship in phenol-soluble modulins using an alanine screen of the phenol-soluble modulin (PSM) *3 peptide. FASEB J 28:153-61
Tong, Steven Y C; Sharma-Kuinkel, Batu K; Thaden, Joshua T et al. (2013) Virulence of endemic nonpigmented northern Australian Staphylococcus aureus clone (clonal complex 75, S. argenteus) is not augmented by staphyloxanthin. J Infect Dis 208:520-7
Surewaard, B G J; de Haas, C J C; Vervoort, F et al. (2013) Staphylococcal alpha-phenol soluble modulins contribute to neutrophil lysis after phagocytosis. Cell Microbiol 15:1427-37
Malachowa, Natalia; Kobayashi, Scott D; Braughton, Kevin R et al. (2013) Mouse model of Staphylococcus aureus skin infection. Methods Mol Biol 1031:109-16
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
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

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