title: Staphylococcus aureus protein A mediates invasion across airway epithelial cells through activation of RhoA GTPase signaling and proteolytic activity.
abstract: Staphyococcus aureus and especially the epidemic methicillin-resistant S. aureus strains cause severe necrotizing pneumonia. The mechanisms whereby these organisms invade across the mucosal epithelial barrier to initiate invasive infection are not well understood. Protein A (SpA), a highly conserved and abundant surface protein of S. aureus, activates TNF receptor 1 and EGF receptor (EGFR) signaling cascades that can perturb the cytoskeleton. We demonstrate that wild-type S. aureus, but not spa mutants, invade across polarized airway epithelial cell monolayers via the paracellular junctions. SpA stimulated a RhoA/ROCK/MLC cascade, resulting in the contraction of the cytoskeleton. SpA(+) but not SpA(-) mutants stimulated activation of EGFR and along with subsequent calpain activity cleaved the membrane-spanning junctional proteins occludin and E-cadherin, facilitating staphylococcal transmigration through the cell-cell junctions. Treatment of polarized human airway epithelial monolayers with inhibitors of ROCK, EGFR, MAPKs, or calpain prevented staphylococcal penetration through the monolayers. In vivo, blocking calpain activity impeded bacterial invasion into the lung parenchyma. Thus, S. aureus exploits multiple receptors available on the airway mucosal surface to facilitate invasion across epithelial barriers.
authors: Department of Pediatrics, College of Physicians and Surgeons Columbia University, New York, New York 10032.
authors: Grace
authors: G
authors: Soong
authors: Department of Pharmacology, College of Physicians and Surgeons Columbia University, New York, New York 10032.
authors: Francis J
authors: FJ
authors: Martin
authors: Department of Pharmacology, College of Physicians and Surgeons Columbia University, New York, New York 10032.
authors: Jarin
authors: J
authors: Chun
authors: Department of Pediatrics, College of Physicians and Surgeons Columbia University, New York, New York 10032.
authors: Taylor S
authors: TS
authors: Cohen
authors: Department of Pediatrics, College of Physicians and Surgeons Columbia University, New York, New York 10032.
authors: Danielle S
authors: DS
authors: Ahn
authors: Department of Pediatrics, College of Physicians and Surgeons Columbia University, New York, New York 10032; Department of Pharmacology, College of Physicians and Surgeons Columbia University, New York, New York 10032. Electronic address: asp7@columbia.edu.
authors: Alice
authors: A
authors: Prince
mesh_terms: D000818:Animals; D015820:Cadherins / Q000235:genetics / Q000378:metabolism; D002154:Calpain / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism; D005260:Female; D006801:Humans; D007365:Intercellular Junctions / Q000235:genetics / Q000378:metabolism; D051379:Mice; D009154:Mutation; D011023:Pneumonia, Staphylococcal / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D011480:Protease Inhibitors / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000235:genetics / Q000378:metabolism; D020545:Respiratory Mucosa / Q000378:metabolism* / Q000382:microbiology; D015398:Signal Transduction; D013205:Staphylococcal Protein A / Q000235:genetics / Q000378:metabolism*; D013211:Staphylococcus aureus / Q000235:genetics / Q000378:metabolism* / Q000472:pathogenicity; D020741:rho GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D054460:rho-Associated Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D020742:rhoA GTP-Binding Protein / Q000235:genetics / Q000378:metabolism*
chemical_list: D015820:Cadherins; D011480:Protease Inhibitors; D047428:Protein Kinase Inhibitors; D047888:Receptors, Tumor Necrosis Factor, Type I; D013205:Staphylococcal Protein A; C506236:Tnfrsf1a protein, mouse; C066737:RHOA protein, human; C512478:EGFR protein, human; C541485:EGFR protein, mouse; D066246:ErbB Receptors; D054460:rho-Associated Kinases; D002154:Calpain; C526380:RhoA protein, mouse; D020741:rho GTP-Binding Proteins; D020742:rhoA GTP-Binding Protein