Staphylococcus aureus is one of the most important human pathogens responsible for infections in both hospital and community settings. Therapeutic options to combat S. aureus infections are limited due to the high level of antibiotic resistance and lack of an effective vaccine. Thus, there is a significant need for the development of effective therapeutics against this organism. Critical to the pathogenic success of S. aureus is the ability of this bacterium to avoid clearance by the host via targeted killing of neutrophils;innate immune cells integral to the control of Staphylococcal infections. Thus, the long-term goal of this research program is to understand the mechanism employed by S. aureus to deplete these critical phagocytes. Recently, we have described the leukotoxin A/B (LukAB) as a virulence factor that plays an integral role in protecting S. aureus from neutrophil-mediated killing by targeting and eliminating these cells. In addition, we have demonstrated that LukAB contributes to the pathogenesis of community-associated, methicillin-resistant Staphylococcus aureus (CA-MRSA) in a murine model of systemic dissemination. We have found that: LukAB is conserved in S. aureus, contributes to the cytotoxicity of a variety of strains including methicilln-sensitive and methicillin- resistant S. aureus, is responsible for the killing of not only neutrophls, but also monocytes, macrophages and dendritic cells, is the most divergent member of the bi-component pore-forming family of toxins found in S. aureus, and it exhibits unique properties that have not been observed by the other leukotoxins. Based on our findings, we propose a model whereby LukAB selectively binds to phagocytes resulting in toxin oligomerization and pore-formation, which ultimately leads to membrane damage and killing of the target cell. The primary goal of this application is to test this model. To this end, we propose three Specific Aims.
In Aim 1 we plan to elucidate the contribution of candidate cellular factors for LukAB tropism towards phagocytes.
In Aim 2 we seek to define functional regions involved in LukAB-mediated toxicity. Lastly, in Aim 3 we propose to determine the mechanism by which LukAB contributes to S. aureus pathogenesis in vivo. To accomplish these Aims, we propose to employ a multidisciplinary approach that combines molecular biology, genetics, immunology, and biochemistry, together with ex vivo and in vivo infection models. Understanding the molecular details of how LukAB mediates targeting and killing of phagocytes is crucial for the development of novel therapeutic modalities to inhibit this toxin as a new approach to combat S. aureus infections.
This application aims to elucidate the mechanism of action of LukAB, a potent leukotoxin produced by Staphylococcus aureus. Information obtained from the studies proposed in this application will pave the way for developing specific inhibitors to target and block the activity of this toxin, which is likely to provide a new avenue for the treatment of infections caused by this important human pathogen.
|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|
|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, András 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|
|Thomsen, Isaac P; Sapparapu, Gopal; James, David B A et al. (2017) Monoclonal Antibodies Against the Staphylococcus aureus Bicomponent Leukotoxin AB Isolated Following Invasive Human Infection Reveal Diverse Binding and Modes of Action. J Infect Dis 215:1124-1131|
|Chapman, Jessica R; Balasubramanian, Divya; Tam, Kayan et al. (2017) Using Quantitative Spectrometry to Understand the Influence of Genetics and Nutritional Perturbations On the Virulence Potential of Staphylococcus aureus. Mol Cell Proteomics 16:S15-S28|
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