title: Superantigens are critical for Staphylococcus aureus Infective endocarditis, sepsis, and acute kidney injury.
abstract: Infective endocarditis and kidney infections are serious complications of Staphylococcus aureus sepsis. We investigated the role of superantigens (SAgs) in the development of lethal sepsis, infective endocarditis, and kidney infections. SAgs cause toxic shock syndrome, but it is unclear if SAgs contribute to infective endocarditis and kidney infections secondary to sepsis. We show in the methicillin-resistant S. aureus strain MW2 that lethal sepsis, infective endocarditis, and kidney infections in rabbits are critically dependent on high-level SAgs. In contrast, the isogenic strain lacking staphylococcal enterotoxin C (SEC), the major SAg in this strain, is attenuated in virulence, while complementation restores disease production. SAgs' role in infective endocarditis appears to be both superantigenicity and direct endothelial cell stimulation. Maintenance of elevated blood pressure by fluid therapy significantly protects from infective endocarditis, possibly through preventing bacterial accumulation on valves and increased SAg elimination. These data should facilitate better methods to manage these serious illnesses.
  
  
  OBJECTIVE
  The Centers for Disease Control and Prevention reported in 2007 that Staphylococcus aureus is the most significant cause of serious infectious diseases in the United States (R. M. Klevens, M. A. Morrison, J. Nadle, S. Petit, K. Gershman, et al., JAMA 298:1763-1771, 2007). Among these infections are sepsis, infective endocarditis, and acute kidney injury. Infective endocarditis occurs in 30 to 60% of patients with S. aureus bacteremia and carries a mortality rate of 40 to 50%. Over the past decades, infective endocarditis outcomes have not improved, and infection rates are steadily increasing (D. H. Bor, S. Woolhandler, R. Nardin, J. Brusch, D. U. Himmelstein, PLoS One 8:e60033, 2013). There is little understanding of the S. aureus virulence factors that are key for infective endocarditis development and kidney abscess formation. We demonstrate that superantigens are critical in the causation of all three infections. We show that their association results from both superantigenicity and direct toxic effects on endothelial cells, the latter likely contributing to delayed endothelium healing. Our studies contribute significantly to understanding the development of these illnesses and are expected to lead to development of important therapies to treat such illnesses.
authors: Department of Microbiology, University of Iowa Carver College of Medicine, Iowa City, Iowa, USA.
authors: Wilmara
authors: W
authors: Salgado-Pabón
authors: Laura
authors: L
authors: Breshears
authors: Adam R
authors: AR
authors: Spaulding
authors: Joseph A
authors: JA
authors: Merriman
authors: Christopher S
authors: CS
authors: Stach
authors: Alexander R
authors: AR
authors: Horswill
authors: Marnie L
authors: ML
authors: Peterson
authors: Patrick M
authors: PM
authors: Schlievert
mesh_terms: D058186:Acute Kidney Injury / Q000382:microbiology* / Q000473:pathology; D000818:Animals; D004195:Disease Models, Animal; D004696:Endocarditis / Q000382:microbiology* / Q000473:pathology; D004768:Enterotoxins / Q000235:genetics / Q000378:metabolism; D017353:Gene Deletion; D005816:Genetic Complementation Test; D055624:Methicillin-Resistant Staphylococcus aureus / Q000235:genetics / Q000472:pathogenicity*; D011817:Rabbits; D018805:Sepsis / Q000382:microbiology* / Q000473:pathology; D013203:Staphylococcal Infections / Q000473:pathology*; D018089:Superantigens / Q000235:genetics / Q000378:metabolism*; D037521:Virulence Factors / Q000235:genetics / Q000378:metabolism*
chemical_list: D004768:Enterotoxins; D018089:Superantigens; D037521:Virulence Factors; C034959:enterotoxin C, staphylococcal
references: J Biol Chem. 2012 Sep 21;287(39):32578-87
references: 22833676
references: Cardiovasc Pathol. 2006 Sep-Oct;15(5):256-263
references: 16979032
references: PLoS One. 2012;7(10):e46389
references: 23115627
references: Clin Infect Dis. 2009 May 15;48 Suppl 4:S231-7
references: 19374578
references: Clin Infect Dis. 2004 Aug 1;39(3):309-17
references: 15306996
references: Infect Immun. 2011 Jan;79(1):342-52
references: 20937760
references: JAMA. 2005 Jun 22;293(24):3012-21
references: 15972563
references: Crit Care Med. 2000 Oct;28(10):3405-11
references: 11057793
references: Crit Care Med. 2006 Oct;34(10):2588-95
references: 16915117
references: Clin Infect Dis. 1993 Apr;16(4):567-73
references: 8513067
references: Infect Immun. 2000 Jun;68(6):3630-4
references: 10816521
references: Medicine (Baltimore). 2012 Mar;91(2):86-94
references: 22391470
references: Nephrol Dial Transplant. 2000 Nov;15(11):1782-7
references: 11071965
references: PLoS Pathog. 2011 Oct;7(10):e1002271
references: 22022262
references: Appl Environ Microbiol. 2013 Apr;79(7):2218-24
references: 23354696
references: J Infect Dis. 2011 Sep 1;204(5):704-13
references: 21844296
references: Protein Eng Des Sel. 2013 Feb;26(2):133-42
references: 23161916
references: J Infect Dis. 1991 Oct;164(4):711-9
references: 1654356
references: J Infect Dis. 2009 Sep 1;200(5):676-8
references: 19653828
references: Arch Intern Med. 2003 Sep 22;163(17):2066-72
references: 14504120
references: PLoS Pathog. 2011 Oct;7(10):e1002307
references: 22028651
references: Annu Rev Microbiol. 2001;55:77-104
references: 11544350
references: Arch Intern Med. 2009 Mar 9;169(5):463-73
references: 19273776
references: Crit Care. 2007;11(2):R31
references: 17331245
references: Front Cell Infect Microbiol. 2012 Feb 21;2:18
references: 22919610
references: J Bacteriol. 2004 Apr;186(8):2430-8
references: 15060046
references: Infect Immun. 1991 Mar;59(3):879-84
references: 1997438
references: J Clin Invest. 2009 Oct;119(10):2868-78
references: 19805915