A primary focus of research in my laboratory investigates 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 an alarming increase in the number of CA-MRSA infections worldwide, which includes an ongoing epidemic of CA-MRSA 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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Intramural Research (Z01)
Project #
1Z01AI001079-01
Application #
7732727
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
1
Fiscal Year
2008
Total Cost
$806,192
Indirect Cost
City
State
Country
United States
Zip Code
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
Kobayashi, Scott D; DeLeo, Frank R (2009) An update on community-associated MRSA virulence. Curr Opin Pharmacol 9:545-51
Queck, Shu Y; Khan, Burhan A; Wang, Rong et al. (2009) Mobile genetic element-encoded cytolysin connects virulence to methicillin resistance in MRSA. PLoS Pathog 5:e1000533
DeLeo, Frank R; Otto, Michael (2008) An antidote for Staphylococcus aureus pneumonia? J Exp Med 205:271-4
Voyich, Jovanka M; Sturdevant, Dan E; DeLeo, Frank R (2008) Analysis of Staphylococcus aureus gene expression during PMN phagocytosis. Methods Mol Biol 431:109-22
Sumby, Paul; Zhang, Shizhen; Whitney, Adeline R et al. (2008) A chemokine-degrading extracellular protease made by group A Streptococcus alters pathogenesis by enhancing evasion of the innate immune response. Infect Immun 76:978-85
Nygaard, Tyler K; DeLeo, Frank R; Voyich, Jovanka M (2008) Community-associated methicillin-resistant Staphylococcus aureus skin infections: advances toward identifying the key virulence factors. Curr Opin Infect Dis 21:147-52
Diep, Binh An; Palazzolo-Ballance, Amy M; Tattevin, Pierre et al. (2008) Contribution of Panton-Valentine leukocidin in community-associated methicillin-resistant Staphylococcus aureus pathogenesis. PLoS One 3:e3198
Otto, Michael; DeLeo, Frank R (2008) Methods molecular biology. Preface. Methods Mol Biol 431:V-VI
Beres, Stephen B; Sesso, Ricardo; Pinto, Sergio Wyton L et al. (2008) Genome sequence of a lancefield group C Streptococcus zooepidemicus strain causing epidemic nephritis: new information about an old disease. PLoS ONE 3:e3026

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