S. aureus is a potent, opportunistic human pathogen that has evolved in a symbiotic relationship with its hosts and is notorious for its ability to cause life-threatening diseases such as sepsis, pneumonia and endocarditis. In 2005 S. aureus was responsible for more death in the US than any other microbial pathogen. S. aureus is unique in that the organism produces over a dozen fibrinogen (Fg) binding cell wall anchored proteins (MSCRAMMs) or small secreted proteins. Many of these proteins act as potent virulence factors and can recruit Fg and assemble a Fg containing coat surrounding and protecting the bacteria from phagocytosis and clearance. We believe that this Fg containing shield represents a key to understand the unique features of S. aureus virulence including the organism?s demonstrated resistance in several active and passive vaccination trials. Consequently, we propose to characterize the staphylococcal Fg binding proteins, their interactions with Fg and the conformational changes leading to the formation of the shield. We will use X-ray crystallography of complexes formed between the bacterial proteins/peptides and Fg fragments/peptides complemented by extensive biochemical studies to characterize the Fg interactions and determining interactive sites. Preliminary results show that the MSCRAMMs use a combination of a primary and a secondary synergistic site to bind Fg with high affinity whereas a common linear Fg binding motif present in two of the secreted proteins exhibits an amazingly high affinity for Fg. The conformational changes induced in Fg upon binding to different staphylococcal proteins will be identified by crystallographic analysis of intact Fg in complex with staphylococcal proteins/peptides and further analyzed in a mouse septicemia model. Based on the detailed information of staphylococcal protein/Fg interactions, we will identify MSCRAMM variants with altered affinity for Fg and explore the possibility that these exhibit altered virulence potentials. Finally, with comprehensive knowledge of staphylococcal Fg interactions, we will generate mAbs that can inhibit Fg binding to staphylococcal proteins. In the future, these mAbs could be developed to useful therapeutic agents.

Public Health Relevance

Staphylococcus aureus is responsible for more death in the US than any other microbe but remains resistant to all vaccination attempts tried so far. Our proposed basic studies on staphylococcal host interactions will provide a possible molecular explanation for the poor outcome of the vaccination attempts and a foundation for the future rational design of effective immuno- preventive and -therapeutic strategies.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
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Bacterial Pathogenesis Study Section (BACP)
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Huntley, Clayton C
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Texas A&M University
Overall Medical
College Station
United States
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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
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
Foster, Timothy J; Geoghegan, Joan A; Ganesh, Vannakambadi K et al. (2014) Adhesion, invasion and evasion: the many functions of the surface proteins of Staphylococcus aureus. Nat Rev Microbiol 12:49-62
Cleaver, J O; You, D; Michaud, D R et al. (2014) Lung epithelial cells are essential effectors of inducible resistance to pneumonia. Mucosal Immunol 7:78-88
Kang, Mingsong; Ko, Ya-Ping; Liang, Xiaowen et al. (2013) Collagen-binding microbial surface components recognizing adhesive matrix molecule (MSCRAMM) of Gram-positive bacteria inhibit complement activation via the classical pathway. J Biol Chem 288:20520-31
Flick, Matthew J; Du, XinLi; Prasad, Joni M et al. (2013) Genetic elimination of the binding motif on fibrinogen for the S. aureus virulence factor ClfA improves host survival in septicemia. Blood 121:1783-94
Ko, Ya-Ping; Kuipers, Annemarie; Freitag, Claudia M et al. (2013) Phagocytosis escape by a Staphylococcus aureus protein that connects complement and coagulation proteins at the bacterial surface. PLoS Pathog 9:e1003816
Ko, Ya-Ping; Liang, Xiaowen; Smith, C Wayne et al. (2011) Binding of Efb from Staphylococcus aureus to fibrinogen blocks neutrophil adherence. J Biol Chem 286:9865-74

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