Staphylococcus aureus is responsible for a large number of hospital- and community-acquired infections worldwide. The rise in incidence of S. aureus infections is primarily due to a combination of increased antibiotic resistance and increased virulence of strains associated with community infections. In the absence of a protective vaccine, studies aimed at dissecting virulence strategies of S. aureus are desperately needed with the hope of identifying novel targets for the generation of new treatments to combat this pathogen. An important pathogenic strategy of S. aureus is the production of exotoxins that target and kill host cells. Among these toxins, S. aureus strains associated with human infections can produce up to four different pore-forming bi-component leukotoxins. The long-term objective of our laboratory is to understand the molecular details by which bi-component leukotoxins influence the pathophysiology of S. aureus infection through targeting cells of the immune system. The present application focuses on one of these toxins, leukocidin ED (LukED). The importance of the proposed research originates from our recent discoveries that LukED: (i) is a critical virulence factor involved in the lethality of mice during S. aureus bloodstream infection, (ii) is required for promoting bacterial replication in vivo, (iii) contributes to S. aureus pathogenesis by targeting and killing immune cells in vivo, and (iv) targets a wide variety of leukocytes in a receptor specific manner. The goals of this research program are to understand the mechanism by which LukED targets different leukocytes, to elucidate the consequences of LukED-mediated cell injury to S. aureus pathogenesis, and to explore the therapeutic benefits of targeting LukED as a new modality to dampen S. aureus virulence. To this end, we propose to employ a multidisciplinary approach that combines biochemistry, cell biology, and immunology techniques with ex vivo tissue culture infection models and in vivo animal models of infection. Results obtained from these studies will provide insight into the molecular details of how S. aureus bi-component pore-forming toxins selectively target and kill host cells and the importance of these toxins to S. aureus pathogenesis.

Public Health Relevance

This application aims to elucidate the mechanism by which LukED contributes to the pathogenesis of S. aureus. Information obtained from these studies is required for the development of novel inhibitors to target and block the activity of this toxin, providing new therapeutic options in the treatment of infections caused by S. aureus.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
1R01AI105129-01A1
Application #
8632282
Study Section
Host Interactions with Bacterial Pathogens Study Section (HIBP)
Program Officer
Huntley, Clayton C
Project Start
2013-12-01
Project End
2018-11-30
Budget Start
2013-12-01
Budget End
2014-11-30
Support Year
1
Fiscal Year
2014
Total Cost
$388,157
Indirect Cost
$159,021
Name
New York University
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
121911077
City
New York
State
NY
Country
United States
Zip Code
10016
Benson, Meredith A; Ohneck, Elizabeth A; Ryan, Chanelle et al. (2014) Evolution of hypervirulence by a MRSA clone through acquisition of a transposable element. Mol Microbiol 93:664-81
Spaan, AndrĂ¡s N; Vrieling, Manouk; Wallet, Pierre et al. (2014) The staphylococcal toxins ?-haemolysin AB and CB differentially target phagocytes by employing specific chemokine receptors. Nat Commun 5:5438
DuMont, Ashley L; Yoong, Pauline; Liu, Xiang et al. (2014) Identification of a crucial residue required for Staphylococcus aureus LukAB cytotoxicity and receptor recognition. Infect Immun 82:1268-76
Alonzo 3rd, Francis; Torres, Victor J (2014) The bicomponent pore-forming leucocidins of Staphylococcus aureus. Microbiol Mol Biol Rev 78:199-230