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
McGuinness, Will A; Kobayashi, Scott D; DeLeo, Frank R (2016) Evasion of Neutrophil Killing by Staphylococcus aureus. Pathogens 5:
Malachowa, Natalia; Kobayashi, Scott D; Porter, Adeline R et al. (2016) Contribution of Staphylococcus aureus Coagulases and Clumping Factor A to Abscess Formation in a Rabbit Model of Skin and Soft Tissue Infection. PLoS One 11:e0158293
Greenlee-Wacker, Mallary; DeLeo, Frank R; Nauseef, William M (2015) How methicillin-resistant Staphylococcus aureus evade neutrophil killing. Curr Opin Hematol 22:30-5
Swindle, Emily J; Brown, Jared M; Rådinger, Madeleine et al. (2015) IFN-γ enhances both the anti-bacterial and the pro-inflammatory response of human mast cells to S. aureus. Immunology :
Malachowa, Natalia; Kobayashi, Scott D; Sturdevant, Daniel E et al. (2015) Insights into the Staphylococcus aureus-host interface: global changes in host and pathogen gene expression in a rabbit skin infection model. PLoS One 10:e0117713
Kobayashi, Scott D; Malachowa, Natalia; DeLeo, Frank R (2015) Pathogenesis of Staphylococcus aureus abscesses. Am J Pathol 185:1518-27
Musser, James M; DeLeo, Frank R (2015) Molecular pathogenesis lessons from the world of infectious diseases research. Am J Pathol 185:1502-4
Deleo, Frank R; Chen, Liang; Porcella, Stephen F et al. (2014) Molecular dissection of the evolution of carbapenem-resistant multilocus sequence type 258 Klebsiella pneumoniae. Proc Natl Acad Sci U S A 111:4988-93
Chen, Liang; Chavda, Kalyan D; Findlay, Jacqueline et al. (2014) Multiplex PCR for identification of two capsular types in epidemic KPC-producing Klebsiella pneumoniae sequence type 258 strains. Antimicrob Agents Chemother 58:4196-9
Kobayashi, Scott D; Sturdevant, Daniel E; Deleo, Frank R (2014) Genome-scale transcript analyses with human neutrophils. Methods Mol Biol 1124:437-50

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