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A Novel Core Genome-Encoded Superantigen Contributes to Lethality of Community-Associated MRSA Necrotizing Pneumonia


Bacterial superantigens (SAg) stimulate T-cell hyper-activation resulting in immune modulation and severe systemic illnesses such as Staphylococcus aureus toxic shock syndrome. However, all known S. aureus SAgs are encoded by mobile genetic elements and are made by only a proportion of strains. Here, we report the discovery of a novel SAg staphylococcal enterotoxin-like toxin X (SElX) encoded in the core genome of 95% of phylogenetically diverse S. aureus strains from human and animal infections, including the epidemic community-associated methicillin-resistant S. aureus (CA-MRSA) USA300 clone. SElX has a unique predicted structure characterized by a truncated SAg B-domain, but exhibits the characteristic biological activities of a SAg including Vβ-specific T-cell mitogenicity, pyrogenicity and endotoxin enhancement. In addition, SElX is expressed by clinical isolates in vitro, and during human, bovine, and ovine infections, consistent with a broad role in S. aureus infections of multiple host species. Phylogenetic analysis suggests that the selx gene was acquired horizontally by a progenitor of the S. aureus species, followed by allelic diversification by point mutation and assortative recombination resulting in at least 17 different alleles among the major pathogenic clones. Of note, SElX variants made by human- or ruminant-specific S. aureus clones demonstrated overlapping but distinct Vβ activation profiles for human and bovine lymphocytes, indicating functional diversification of SElX in different host species. Importantly, SElX made by CA-MRSA USA300 contributed to lethality in a rabbit model of necrotizing pneumonia revealing a novel virulence determinant of CA-MRSA disease pathogenesis. Taken together, we report the discovery and characterization of a unique core genome-encoded superantigen, providing new insights into the evolution of pathogenic S. aureus and the molecular basis for severe infections caused by the CA-MRSA USA300 epidemic clone.


Vyšlo v časopise: A Novel Core Genome-Encoded Superantigen Contributes to Lethality of Community-Associated MRSA Necrotizing Pneumonia. PLoS Pathog 7(10): e32767. doi:10.1371/journal.ppat.1002271
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.ppat.1002271

Souhrn

Bacterial superantigens (SAg) stimulate T-cell hyper-activation resulting in immune modulation and severe systemic illnesses such as Staphylococcus aureus toxic shock syndrome. However, all known S. aureus SAgs are encoded by mobile genetic elements and are made by only a proportion of strains. Here, we report the discovery of a novel SAg staphylococcal enterotoxin-like toxin X (SElX) encoded in the core genome of 95% of phylogenetically diverse S. aureus strains from human and animal infections, including the epidemic community-associated methicillin-resistant S. aureus (CA-MRSA) USA300 clone. SElX has a unique predicted structure characterized by a truncated SAg B-domain, but exhibits the characteristic biological activities of a SAg including Vβ-specific T-cell mitogenicity, pyrogenicity and endotoxin enhancement. In addition, SElX is expressed by clinical isolates in vitro, and during human, bovine, and ovine infections, consistent with a broad role in S. aureus infections of multiple host species. Phylogenetic analysis suggests that the selx gene was acquired horizontally by a progenitor of the S. aureus species, followed by allelic diversification by point mutation and assortative recombination resulting in at least 17 different alleles among the major pathogenic clones. Of note, SElX variants made by human- or ruminant-specific S. aureus clones demonstrated overlapping but distinct Vβ activation profiles for human and bovine lymphocytes, indicating functional diversification of SElX in different host species. Importantly, SElX made by CA-MRSA USA300 contributed to lethality in a rabbit model of necrotizing pneumonia revealing a novel virulence determinant of CA-MRSA disease pathogenesis. Taken together, we report the discovery and characterization of a unique core genome-encoded superantigen, providing new insights into the evolution of pathogenic S. aureus and the molecular basis for severe infections caused by the CA-MRSA USA300 epidemic clone.


Zdroje

1. ThomasDChouSDauwalderOLinaG 2007 Diversity in Staphylococcus aureus enterotoxins. Chem Immunol Allergy 93 24 41

2. DingesMMOrwinPMSchlievertPM 2000 Exotoxins of Staphylococcus aureus. Clin Microbiol Rev 13 16 34

3. ThomasDDauwalderOBrunVBadiouCFerryT 2009 Staphylococcus aureus superantigens elicit redundant and extensive human Vbeta patterns. Infect Immun 77 2043 2050

4. OnoHKOmoeKImanishiKiIwakabeYHuD-L 2008 Identification and Characterization of Two Novel Staphylococcal Enterotoxins, Types S and T. Infect Immun 76 4999 5005

5. SeoKSBohachGA 2007 Staphylococcus aureus; DoyleMPLBMontvilleTJ Washington D.C ASM Press

6. FraserJDProftT 2008 The bacterial superantigen and superantigen-like proteins. Immunol Rev 225 226 243

7. ChoiYWKotzinBHerronLCallahanJMarrackP 1989 Interaction of Staphylococcus aureus toxin “superantigens” with human T cells. Proc Natl Acad Sci U S A 86 8941 8945

8. DellabonaPPeccoudJKapplerJMarrackPBenoistC 1990 Superantigens interact with MHC class II molecules outside of the antigen groove. Cell 62 1115 1121

9. DrakeCGKotzinBL 1992 Superantigens: biology, immunology, and potential role in disease. J Clin Immunol 12 149 162

10. KawabeYOchiA 1990 Selective anergy of V beta 8+,CD4+ T cells in Staphylococcus enterotoxin B-primed mice. J Exp Med 172 1065 1070

11. FitzgeraldJRMondaySRFosterTJBohachGAHartiganPJ 2001 Characterization of a putative pathogenicity island from bovine Staphylococcus aureus encoding multiple superantigens. J Bacteriol 183 63 70

12. JarraudSPeyratMALimATristanABesM 2001 egc, a highly prevalent operon of enterotoxin gene, forms a putative nursery of superantigens in Staphylococcus aureus. J Immunol 166 669 677

13. JohnsMBJrKhanSA 1988 Staphylococcal enterotoxin B gene is associated with a discrete genetic element. J Bacteriol 170 4033 4039

14. Ben ZakourNLGuinaneCMFitzgeraldJR 2008 Pathogenomics of the staphylococci: insights into niche adaptation and the emergence of new virulent strains. FEMS Microbiol Lett 289 1 12

15. SmythDSHartiganPJMeaneyWJFitzgeraldJRDeobaldCF 2005 Superantigen genes encoded by the egc cluster and SaPIbov are predominant among Staphylococcus aureus isolates from cows, goats, sheep, rabbits and poultry. J Med Microbiol 54 401 411

16. OmoeKHuDLTakahashi-OmoeHNakaneAShinagawaK 2005 Comprehensive analysis of classical and newly described staphylococcal superantigenic toxin genes in Staphylococcus aureus isolates. FEMS Microbiol Lett 246 191 198

17. ChambersHF 2005 Community-associated MRSA--resistance and virulence converge. N Engl J Med 352 1485 1487

18. DaumRSItoTHiramatsuKHussainFMongkolrattanothaiK 2002 A novel methicillin-resistance cassette in community-acquired methicillin-resistant Staphylococcus aureus isolates of diverse genetic backgrounds. J Infect Dis 186 1344 1347

19. KlevensRMMorrisonMANadleJPetitSGershmanK 2007 Invasive methicillin-resistant Staphylococcus aureus infections in the United States. JAMA 298 1763 1771

20. FrancisJSDohertyMCLopatinUJohnstonCPSinhaG 2005 Severe community-onset pneumonia in healthy adults caused by methicillin-resistant Staphylococcus aureus carrying the Panton-Valentine leukocidin genes. Clin Infect Dis 40 100 107

21. DiepBAGillSRChangRFPhanTHChenJH 2006 Complete genome sequence of USA300, an epidemic clone of community-acquired meticillin-resistant Staphylococcus aureus. Lancet 367 731 739

22. KwanTLiuJDuBowMGrosPPelletierJ 2005 The complete genomes and proteomes of 27 Staphylococcus aureus bacteriophages. Proc Natl Acad Sci U S A 102 5174 5179

23. HeathLvan der WaltEVarsaniAMartinDP 2006 Recombination Patterns in Aphthoviruses Mirror Those Found in Other Picornaviruses. J Virol 80 11827 11832

24. KelleyLASternbergMJ 2009 Protein structure prediction on the Web: a case study using the Phyre server. Nat Protoc 4 363 371

25. BurroughsAMBalajiSIyerLMAravindL 2007 Small but versatile: the extraordinary functional and structural diversity of the beta-grasp fold. Biol Direct 2 18

26. McCormickJKTrippTJLleraASSundbergEJDingesMM 2003 Functional Analysis of the TCR Binding Domain of Toxic Shock Syndrome Toxin-1 Predicts Further Diversity in MHC Class II/Superantigen/TCR Ternary Complexes. J Immunol 171 1385 1392

27. SeoKSParkJYTermanDSBohachGA 2010 A quantitative real time PCR method to analyze T cell receptor Vbeta subgroup expansion by staphylococcal superantigens. J Transl Med 8 2

28. DeringerJRElyRJMondaySRStauffacherCVBohachGA 1997 Vbeta-dependent stimulation of bovine and human T cells by host-specific staphylococcal enterotoxins. Infect Immun 65 4048 4054

29. ConnelleyTAertsJLawAMorrisonWI 2009 Genomic analysis reveals extensive gene duplication within the bovine TRB locus. BMC Genomics 10 192

30. ElsikCGTellamRLWorleyKCGibbsRAMuznyDM 2009 The genome sequence of taurine cattle: a window to ruminant biology and evolution. Science 324 522 528

31. HeroldBCImmergluckLCMarananMCLauderdaleDSGaskinRE 1998 Community-acquired methicillin-resistant Staphylococcus aureus in children with no identified predisposing risk. JAMA 279 593 598

32. SomervilleGABeresSBFitzgeraldJRDeLeoFRColeRL 2002 In Vitro Serial Passage of Staphylococcus aureus: Changes in Physiology, Virulence Factor Production, and agr Nucleotide Sequence. J Bacteriol 184 1430 1437

33. StrandbergKLRotschaferJHVetterSMBuonpaneRAKranzDM 2010 Staphylococcal superantigens cause lethal pulmonary disease in rabbits. J Infect Dis 202 1690 1697

34. LindsayJAMooreCEDayNPPeacockSJWitneyAA 2006 Microarrays reveal that each of the ten dominant lineages of Staphylococcus aureus has a unique combination of surface-associated and regulatory genes. J Bacteriol 188 669 676

35. HoldenMTFeilEJLindsayJAPeacockSJDayNP 2004 Complete genomes of two clinical Staphylococcus aureus strains: evidence for the rapid evolution of virulence and drug resistance. Proc Natl Acad Sci U S A 101 9786 9791

36. ProftTMoffattSLWellerKDPatersonAMartinD 2000 The streptococcal superantigen SMEZ exhibits wide allelic variation, mosaic structure, and significant antigenic variation. J Exp Med 191 1765 1776

37. LowderBVGuinaneCMBen ZakourNLWeinertLAConway-MorrisA 2009 Recent human-to-poultry host jump, adaptation, and pandemic spread of Staphylococcus aureus. Proc Natl Acad Sci U S A 106 19545 19550

38. GuinaneCMBen ZakourNLTormo-MasMAWeinertLALowderBV 2010 Evolutionary Genomics of Staphylococcus aureus Reveals Insights into the Origin and Molecular Basis of Ruminant Host Adaptation. Genome Biol Evol 2 454 466

39. MarrJCLyonJDRobersonJRLupherMDavisWC 1993 Characterization of novel type C staphylococcal enterotoxins: biological and evolutionary implications. Infect Immun 61 4254 4262

40. FeilEJCooperJEGrundmannHRobinsonDAEnrightMC 2003 How clonal is Staphylococcus aureus? J Bacteriol 185 3307 3316

41. RobinsonDAMonkABCooperJEFeilEJEnrightMC 2005 Evolutionary Genetics of the Accessory Gene Regulator (agr) Locus in Staphylococcus aureus. J Bacteriol 187 8312 8321

42. WatanabeSItoTSasakiTLiSUchiyamaI 2009 Genetic diversity of staphylocoagulase genes (coa): insight into the evolution of variable chromosomal virulence factors in Staphylococcus aureus. PLoS One 4 e5714

43. LiMDiepBAVillaruzAEBraughtonKRJiangX 2009 Evolution of virulence in epidemic community-associated methicillin-resistant Staphylococcus aureus. Proc Natl Acad Sci U S A 106 5883 5888

44. OttoM 2010 Basis of virulence in community-associated methicillin-resistant Staphylococcus aureus. Annu Rev Microbiol 64 143 162

45. LiMCheungGYHuJWangDJooHS 2010 Comparative analysis of virulence and toxin expression of global community-associated methicillin-resistant Staphylococcus aureus strains. J Infect Dis 202 1866 1876

46. SchlievertPM 2009 Cytolysins, superantigens, and pneumonia due to community-associated methicillin-resistant Staphylococcus aureus. J Infect Dis 200 676 678

47. MontgomeryCPBoyle-VavraSAdemPVLeeJCHusainAN 2008 Comparison of virulence in community-associated methicillin-resistant Staphylococcus aureus pulsotypes USA300 and USA400 in a rat model of pneumonia. J Infect Dis 198 561 570

48. Labandeira-ReyMCouzonFBoissetSBrownELBesM 2007 Staphylococcus aureus Panton-Valentine leukocidin causes necrotizing pneumonia. Science 315 1130 1133

49. DiepBAChanLTattevinPKajikawaOMartinTR 2010 Polymorphonuclear leukocytes mediate Staphylococcus aureus Panton-Valentine leukocidin-induced lung inflammation and injury. Proc Natl Acad Sci U S A 107 5587 5592

50. Bubeck WardenburgJBaeTOttoMDeleoFRSchneewindO 2007 Poring over pores: alpha-hemolysin and Panton-Valentine leukocidin in Staphylococcus aureus pneumonia. Nat Med 13 1405 1406

51. AssimacopoulosAPStrandbergKLRotschaferJHSchlievertPM 2009 Extreme pyrexia and rapid death due to Staphylococcus aureus infection: analysis of 2 cases. Clin Infect Dis 48 612 614

52. DingesMMSchlievertPM 2001 Comparative analysis of lipopolysaccharide-induced tumor necrosis factor alpha activity in serum and lethality in mice and rabbits pretreated with the staphylococcal superantigen toxic shock syndrome toxin 1. Infect Immun 69 7169 7172

53. TamuraKDudleyJNeiMKumarS 2007 MEGA4: Molecular Evolutionary Genetics Analysis (MEGA) Software Version 4.0. Mol Biol Evol 24 1596 1599

54. DeLanoWL 2002 The PyMOL Molecular Graphics System. ScientificD San Carlos, CA, USA

55. WaterhouseAMProcterJBMartinDMClampMBartonGJ 2009 Jalview Version 2--a multiple sequence alignment editor and analysis workbench. Bioinformatics 25 1189 1191

56. SterCGilbertFBCochardTPoutrelB 2005 Transcriptional profiles of regulatory and virulence factors of Staphylococcus aureus of bovine origin: oxygen impact and strain-to-strain variations. Mol Cell Probes 19 227 235

57. DagaSShepherdJCallaghanGHungRDawsonD 2011 Platelet receptor polymorphisms do not influence Staphylococcus aureus-platelet interactions or infective endocarditis. Microbes Infect 13 216 225

58. Le MaréchalCJanGEvenSMcCullochJAAzevedoV 2009 Development of serological proteome analysis of mastitis by Staphylococcus aureus in ewes. J Microbiol Methods 79 131 136

59. MemmiGFilipeSRPinhoMGFuZCheungA 2008 Staphylococcus aureus PBP4 is essential for beta-lactam resistance in community-acquired methicillin-resistant strains. Antimicrob Agents Chemother 52 3955 3966

60. SchlievertPM 1982 Enhancement of host susceptibility to lethal endotoxin shock by staphylococcal pyrogenic exotoxin type C. Infect Immun 36 123 128

61. ParsonnetJGillisZARichterAGPierGB 1987 A rabbit model of toxic shock syndrome that uses a constant, subcutaneous infusion of toxic shock syndrome toxin 1. Infect Immun 55 1070 1076

62. GoddeerisBMMorrisonWI 1988 Techniques for the generation, cloning, and characterization of bovine cytotoxic T cells specific for the protozoan Theileria parva. Methods Cell Sci 11 101 110

63. BarsumianELSchlievertPMWatsonDW 1978 Nonspecific and specific immunological mitogenicity by group A streptococcal pyrogenic exotoxins. Infect Immun 22 681 688

64. RozenS 2000 Primer3 on the WWW for general users and for biologist programmers. Krawetz SMSe Bioinformatics Methods and Protocols: Methods in Molecular Biology Totowa, NJ Humana Press 365 386

65. ArdenBClarkSPKabelitzDMakTW 1995 Human T-cell receptor variable gene segment families. Immunogenetics 42 455 500

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Hygiena a epidemiológia Infekčné lekárstvo Laboratórium

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