A number of different microorganisms have been demonstrated to bind various adhesive extracellular matrix proteins. These interactions seem to represent host tissue adhesion mechanisms which are crucial initial steps in the development of infection. The long range goal for this research program is to design inhibitors of the bacteria-fibronectin interaction which would prevent or reverse host tissue adherence and thereby the development of infection. A fibronectin receptor from Staphylococcus aureus has been isolated, the corresponding gene has been cloned and sequenced and peptides deduced from this nucleotide sequence have been shown to inhibit the binding of Staphylococcus aureus to fibronectin matrices. In the proposed studies, we will immunologically and functionally compare the isolated receptor with those obtained from other strains of S. aureus as well as from other species of staphylococci and streptococci. The amino acids in the S. aureus receptor essential for binding to fibronectin will be defined and small peptides synthesized which inhibit the binding of bacteria to fibronectin matrices. The interaction between receptors and fibronectin will be characterized in detail by x-ray crystallographic analyses of individual components as well as appropriate complexes. This will hopefully form the basis for the synthesis of new types of inhibitors. The virulence of fibronectin receptors will be determined by assaying transposon mutants which differ from the wild type cells only in fibronectin receptor activity. Fibronectin receptors will also be isolated, characterized and the corresponding genes cloned from different species of streptococci and coagulase negative staphylococci. Fibronectin binding sites in these receptors will be identified and synthetic peptides mimicking these sites will be tested for their ability to interfere with fibronectin binding. The effect of bacterial receptors on the normal behavior of eukaryotic cells, especially in terms of matrix assembly, will be analyzed.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
7R01AI020624-09
Application #
3130407
Study Section
Pathobiochemistry Study Section (PBC)
Project Start
1989-12-01
Project End
1994-11-30
Budget Start
1992-06-01
Budget End
1992-11-30
Support Year
9
Fiscal Year
1992
Total Cost
Indirect Cost
Name
Texas Agrilife Research
Department
Type
Schools of Earth Sciences/Natur
DUNS #
110521739
City
College Station
State
TX
Country
United States
Zip Code
77843
Casillas-Ituarte, Nadia N; Cruz, Carlos H B; Lins, Roberto D et al. (2017) Amino acid polymorphisms in the fibronectin-binding repeats of fibronectin-binding protein A affect bond strength and fibronectin conformation. J Biol Chem 292:8797-8810
Garcia, Brandon L; Zhi, Hui; Wager, Beau et al. (2016) Borrelia burgdorferi BBK32 Inhibits the Classical Pathway by Blocking Activation of the C1 Complement Complex. PLoS Pathog 12:e1005404
Arora, Srishtee; Uhlemann, Anne-Catrin; Lowy, Franklin D et al. (2016) A Novel MSCRAMM Subfamily in Coagulase Negative Staphylococcal Species. Front Microbiol 7:540
Ganesh, Vannakambadi K; Liang, Xiaowen; Geoghegan, Joan A et al. (2016) Lessons from the Crystal Structure of the S. aureus Surface Protein Clumping Factor A in Complex With Tefibazumab, an Inhibiting Monoclonal Antibody. EBioMedicine 13:328-338
Liang, Xiaowen; Garcia, Brandon L; Visai, Livia et al. (2016) Allosteric Regulation of Fibronectin/?5?1 Interaction by Fibronectin-Binding MSCRAMMs. PLoS One 11:e0159118
Kuipers, Annemarie; Stapels, Daphne A C; Weerwind, Lleroy T et al. (2016) The Staphylococcus aureus polysaccharide capsule and Efb-dependent fibrinogen shield act in concert to protect against phagocytosis. Microbiology 162:1185-94
Ko, Ya-Ping; Kang, Mingsong; Ganesh, Vannakambadi K et al. (2016) Coagulase and Efb of Staphylococcus aureus Have a Common Fibrinogen Binding Motif. MBio 7:e01885-15
Prasad, Joni M; Gorkun, Oleg V; Raghu, Harini et al. (2015) Mice expressing a mutant form of fibrinogen that cannot support fibrin formation exhibit compromised antimicrobial host defense. Blood 126:2047-58
Somarajan, Sudha R; La Rosa, Sabina Leanti; Singh, Kavindra V et al. (2015) The fibronectin-binding protein Fnm contributes to adherence to extracellular matrix components and virulence of Enterococcus faecium. Infect Immun 83:4653-61
Galloway-Peña, Jessica R; Liang, Xiaowen; Singh, Kavindra V et al. (2015) The identification and functional characterization of WxL proteins from Enterococcus faecium reveal surface proteins involved in extracellular matrix interactions. J Bacteriol 197:882-92

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