The binding of streptococci to human platelets is a postulated central mechanism in the pathogenesis of infective endocarditis. Bacterium-platelet binding may be important both for the initial attachment of blood-borne organisms to the valve surface, and for the subsequent formation of macroscopic vegetations. The goal of this project is to characterize further the molecular basis for direct platelet binding by Streptococcus gordonii, and the role of binding in the pathogenesis of endocarditis. We have identified two loci of S. gordonii strain M99 that mediate the direct binding of this organism to human platelets in vitro. The first locus (gspA) encodes a 117 kDa cell wall-associated protein that may function as an adhesin. The second locus appears to be an operon (gspB-secY2A2) encoding a 286 kDa cell wall anchored protein (GspB) that is also a likely platelet binding protein. In addition, this operon contains genes (secA2 and secY2) that are required for the export of GspB. We now seek to further examine the role of these genes and their products in mediating binding to platelets. Our first goal is to characterize more extensively these loci by confirming that expression of gspA or gspB is linked to platelet binding. This work will include complementation studies of gspA and gspB mutants, expression of GspA or GspB in Lactococcus lactis and studying its effects on platelet binding by that organism, and additional mapping of the gspB-secY2A2 operon. We will then purify GspA and GspB, and examine the binding properties of each protein with human platelets in vitro, thereby determining if binding resembles a receptor-ligand interaction. Purified GspA and GspB will also be used to identify their respective platelet binding sites. To assess the role of these adhesins in the pathogenesis of endocarditis, we will compare the virulence of M99 and selected mutants in a rabbit model of endocardial infection. By characterizing streptococcal adhesins for platelets, this research will further define the role of platelet binding in the pathogenesis of endocarditis. In addition, it may identify novel targets for new preventative or therapeutic strategies.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
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Bacteriology and Mycology Subcommittee 2 (BM)
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Rubin, Fran A
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Northern California Institute Research & Education
San Francisco
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Bensing, Barbara A; Li, Qiongyu; Park, Dayoung et al. (2018) Streptococcal Siglec-like adhesins recognize different subsets of human plasma glycoproteins: implications for infective endocarditis. Glycobiology 28:601-611
Yakovenko, Olga; Nunez, Jamie; Bensing, Barbara et al. (2018) Serine-Rich Repeat Adhesins Mediate Shear-Enhanced Streptococcal Binding to Platelets. Infect Immun 86:
Yim, Juwon; Smith, Jordan R; Singh, Nivedita B et al. (2017) Evaluation of daptomycin combinations with cephalosporins or gentamicin against Streptococcus mitis group strains in an in vitro model of simulated endocardial vegetations (SEVs). J Antimicrob Chemother 72:2290-2296
Lin, Shun-Mei; Jang, A-Yeung; Zhi, Yong et al. (2017) Vaccination With a Latch Peptide Provides Serotype-Independent Protection Against Group B Streptococcus Infection in Mice. J Infect Dis 217:93-102
Garcia-de-la-Maria, C; Xiong, Y Q; Pericas, J M et al. (2017) Impact of High-Level Daptomycin Resistance in the Streptococcus mitis Group on Virulence and Survivability during Daptomycin Treatment in Experimental Infective Endocarditis. Antimicrob Agents Chemother 61:
Mishra, Nagendra N; Tran, Truc T; Seepersaud, Ravin et al. (2017) Perturbations of Phosphatidate Cytidylyltransferase (CdsA) Mediate Daptomycin Resistance in Streptococcus mitis/oralis by a Novel Mechanism. Antimicrob Agents Chemother 61:
Seepersaud, Ravin; Sychantha, David; Bensing, Barbara A et al. (2017) O-acetylation of the serine-rich repeat glycoprotein GspB is coordinated with accessory Sec transport. PLoS Pathog 13:e1006558
Bensing, Barbara A; Loukachevitch, Lioudmila V; McCulloch, Kathryn M et al. (2016) Structural Basis for Sialoglycan Binding by the Streptococcus sanguinis SrpA Adhesin. J Biol Chem 291:7230-40
Bensing, Barbara A; Khedri, Zahra; Deng, Lingquan et al. (2016) Novel aspects of sialoglycan recognition by the Siglec-like domains of streptococcal SRR glycoproteins. Glycobiology 26:1222-1234
Loukachevitch, Lioudmila V; Bensing, Barbara A; Yu, Hai et al. (2016) Structures of the Streptococcus sanguinis SrpA Binding Region with Human Sialoglycans Suggest Features of the Physiological Ligand. Biochemistry :

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