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) contribues 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 #
5R01AI105129-03
Application #
8960333
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
2015-12-01
Budget End
2016-11-30
Support Year
3
Fiscal Year
2016
Total Cost
Indirect Cost
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
Copin, Richard; Shopsin, Bo; Torres, Victor J (2018) After the deluge: mining Staphylococcus aureus genomic data for clinical associations and host-pathogen interactions. Curr Opin Microbiol 41:43-50
Blake, Kimbria J; Baral, Pankaj; Voisin, Tiphaine et al. (2018) Staphylococcus aureus produces pain through pore-forming toxins and neuronal TRPV1 that is silenced by QX-314. Nat Commun 9:37
Harper, Lamia; Balasubramanian, Divya; Ohneck, Elizabeth A et al. (2018) Staphylococcus aureus Responds to the Central Metabolite Pyruvate To Regulate Virulence. MBio 9:
Mlynek, Kevin D; Sause, William E; Moormeier, Derek E et al. (2018) Nutritional Regulation of the Sae Two-Component System by CodY in Staphylococcus aureus. J Bacteriol 200:
Bhattacharya, Mohini; Berends, Evelien T M; Chan, Rita et al. (2018) Staphylococcus aureus biofilms release leukocidins to elicit extracellular trap formation and evade neutrophil-mediated killing. Proc Natl Acad Sci U S A 115:7416-7421
Reyes-Robles, Tamara; Torres, Victor J (2017) Staphylococcus aureus Pore-Forming Toxins. Curr Top Microbiol Immunol 409:121-144
Juttukonda, Lillian J; Berends, Evelien T M; Zackular, Joseph P et al. (2017) Dietary Manganese Promotes Staphylococcal Infection of the Heart. Cell Host Microbe 22:531-542.e8
Lubkin, Ashira; Torres, Victor J (2017) Bacteria and endothelial cells: a toxic relationship. Curr Opin Microbiol 35:58-63
Roberts, Christina A; Al-Tameemi, Hassan M; Mashruwala, Ameya A et al. (2017) The Suf Iron-Sulfur Cluster Biosynthetic System Is Essential in Staphylococcus aureus, and Decreased Suf Function Results in Global Metabolic Defects and Reduced Survival in Human Neutrophils. Infect Immun 85:
Spaan, AndrĂ¡s N; van Strijp, Jos A G; Torres, Victor J (2017) Leukocidins: staphylococcal bi-component pore-forming toxins find their receptors. Nat Rev Microbiol 15:435-447

Showing the most recent 10 out of 27 publications