Sigma Factor SigB Is Crucial to Mediate Adaptation during Chronic Infections

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Staphylococcus aureus is a frequent pathogen of severe invasive infections that can develop into chronicity and become extremely difficult to eradicate. Chronic infections have been highly associated with altered bacterial phenotypes, i.e., the small colony variants (SCVs) that dynamically appear after bacterial host cell invasion and are highly adapted for intracellular long-term persistence. In this study, we analyzed the underlying mechanisms of the bacterial switching and adaptation process by investigating the functions of the global S. aureus regulators agr, sarA and SigB. We demonstrate that a tight crosstalk between these factors supports the bacteria at any stage of the infection and that SigB is the crucial factor for bacterial adaptation during long-term persistence. In the acute phase, the bacteria require active agr and sarA systems to induce inflammation and cytotoxicity, and to establish an infection at high bacterial numbers. In the chronic stage of infection, SigB downregulates the aggressive bacterial phenotype and mediates the formation of dynamic SCV-phenotypes. Consequently, we describe SigB as a crucial factor for bacterial adaptation and persistence, which represents a possible target for therapeutic interventions against chronic infections.

Vyšlo v časopise: Sigma Factor SigB Is Crucial to Mediate Adaptation during Chronic Infections. PLoS Pathog 11(4): e32767. doi:10.1371/journal.ppat.1004870
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.ppat.1004870

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Zdroje

1. Lowy FD (1998) Staphylococcus aureus infections. N Engl J Med 339: 520–32. 9709046

2. Lew DP, Waldvogel FA (2004) Osteomyelitis. Lancet 364: 369–379. 15276398

3. Werdan K, Dietz S, Löffler B, Niemann S, Bushnaq H et al. (2014) Mechanisms of infective endocarditis: pathogen-host interaction and risk states. Nat Rev Cardiol 11: 35–50. doi: 10.1038/nrcardio.2013.174 24247105

4. Proctor RA, von Eiff C, Kahl BC, Becker K, McNamara P et al. (2006) Small colony variants: a pathogenic form of bacteria that facilitates persistent and recurrent infections. Nat Rev Microbiol 4: 295–305. 16541137

5. Otto M (2014) Staphylococcus aureus toxins. Curr Opin Microbiol 17: 32–37. doi: 10.1016/j.mib.2013.11.004 24581690

6. Wang R, Braughton KR, Kretschmer D, Bach TH, Queck SY et al. (2007) Identification of novel cytolytic peptides as key virulence determinants for community-associated MRSA. Nat Med 13: 1510–1514. 17994102

7. Ellington JK, Reilly SS, Ramp WK, Smeltzer MS, Kellam JF et al. (1999) Mechanisms of Staphylococcus aureus invasion of cultured osteoblasts. Microb Pathog 26: 317–323. 10343060

8. Haslinger-Löffler B, Kahl BC, Grundmeier M, Strangfeld K, Wagner B et al. (2005) Multiple virulence factors are required for Staphylococcus aureus-induced apoptosis in endothelial cells. Cell Microbiol 7: 1087–1097. 16008576

9. Tuchscherr L, Medina E, Hussain M, Völker W, Heitmann V et al. (2011) Staphylococcus aureus phenotype switching: an effective bacterial strategy to escape host immune response and establish a chronic infection. EMBO Mol Med 3: 129–141. doi: 10.1002/emmm.201000115 21268281

10. Amano A, Nakagawa I, Yoshimori T (2006) Autophagy in innate immunity against intracellular bacteria. J Biochem 140: 161–166. 16954534

11. Deretic V, Levine B (2009) Autophagy, immunity, and microbial adaptations. Cell Host Microbe 5: 527–549. doi: 10.1016/j.chom.2009.05.016 19527881

12. Sinha B, Fraunholz M (2010) Staphylococcus aureus host cell invasion and post-invasion events. Int J Med Microbiol 300: 170–175. doi: 10.1016/j.ijmm.2009.08.019 19781990

13. Grosz M, Kolter J, Paprotka K, Winkler AC, Schafer D et al. (2013) Cytoplasmic replication of Staphylococcus aureus upon phagosomal escape triggered by phenol-soluble modulin alpha. Cell Microbiol.

14. Tuchscherr L, Heitmann V, Hussain M, Viemann D, Roth J et al. (2010) Staphylococcus aureus Small-Colony Variants Are Adapted Phenotypes for Intracellular Persistence. J Infect Dis 202: 1031–1040. doi: 10.1086/656047 20715929

15. Bayer MG, Heinrichs JH, Cheung AL (1996) The molecular architecture of the sar locus in Staphylococcus aureus. J Bacteriol 178: 4563–70. 8755885

16. Bischoff M, Dunman P, Kormanec J, Macapagal D, Murphy E et al. (2004) Microarray-based analysis of the Staphylococcus aureus sigmaB regulon. J Bacteriol 186: 4085–4099. 15205410

17. Cheung AL, Nishina KA, Trotonda MP, Tamber S (2008) The SarA protein family of Staphylococcus aureus. Int J Biochem Cell Biol 40: 355–361. 18083623

18. Recsei P, Kreiswirth B, O'Reilly M, Schlievert P, Gruss A et al. (1986) Regulation of exoprotein gene expression in Staphylococcus aureus by agar. Mol Gen Genet 202: 58–61. 3007938

19. Novick RP, Geisinger E (2008) Quorum sensing in staphylococci. Annu Rev Genet 42: 541–564. doi: 10.1146/annurev.genet.42.110807.091640 18713030

20. Queck SY, Jameson-Lee M, Villaruz AE, Bach TH, Khan BA et al. (2008) RNAIII-independent target gene control by the agr quorum-sensing system: insight into the evolution of virulence regulation in Staphylococcus aureus. Mol Cell 32: 150–158. doi: 10.1016/j.molcel.2008.08.005 18851841

21. Bantel H, Sinha B, Domschke W, Peters G, Schulze-Osthoff K et al. (2001) alpha-Toxin is a mediator of Staphylococcus aureus-induced cell death and activates caspases via the intrinsic death pathway independently of death receptor signaling. J Cell Biol 155: 637–48. 11696559

22. Bhakdi S, Tranum-Jensen J (1991) Alpha-toxin of Staphylococcus aureus. Microbiol Rev 55: 733–751. 1779933

23. Rasigade JP, Trouillet-Assant S, Ferry T, Diep BA, Sapin A et al. (2013) PSMs of hypervirulent Staphylococcus aureus act as intracellular toxins that kill infected osteoblasts. PLoS ONE 8: e63176. doi: 10.1371/journal.pone.0063176 23690994

24. Cheung AL, Koomey JM, Butler CA, Projan SJ, Fischetti VA (1992) Regulation of exoprotein expression in Staphylococcus aureus by a locus (sar) distinct from agr. Proc Natl Acad Sci U S A 89: 6462–6. 1321441

25. Cheung AL, Bayer AS, Zhang G, Gresham H, Xiong YQ (2004) Regulation of virulence determinants in vitro and in vivo in Staphylococcus aureus. FEMS Immunol Med Microbiol 40: 1–9. 14734180

26. Blevins JS, Elasri MO, Allmendinger SD, Beenken KE, Skinner RA et al. (2003) Role of sarA in the pathogenesis of Staphylococcus aureus musculoskeletal infection. Infect Immun 71: 516–523. 12496203

27. Cheung AL, Eberhardt KJ, Chung E, Yeaman MR, Sullam PM et al. (1994) Diminished virulence of a sar-/agr- mutant of Staphylococcus aureus in the rabbit model of endocarditis. J Clin Invest 94: 1815–1822. 7962526

28. van Wamel W., Xiong YQ, Bayer AS, Yeaman MR, Nast CC et al. (2002) Regulation of Staphylococcus aureus type 5 capsular polysaccharides by agr and sarA in vitro and in an experimental endocarditis model. Microb Pathog 33: 73–79. 12202106

29. Beenken KE, Blevins JS, Smeltzer MS (2003) Mutation of sarA in Staphylococcus aureus limits biofilm formation. Infect Immun 71: 4206–4211. 12819120

30. Blevins JS, Gillaspy AF, Rechtin TM, Hurlburt BK, Smeltzer MS (1999) The Staphylococcal accessory regulator (sar) represses transcription of the Staphylococcus aureus collagen adhesin gene (cna) in an agr-independent manner. Mol Microbiol 33: 317–326. 10411748

31. Hecker M, Reder A, Fuchs S, Pagels M, Engelmann S (2009) Physiological proteomics and stress/starvation responses in Bacillus subtilis and Staphylococcus aureus. Res Microbiol 160: 245–258. doi: 10.1016/j.resmic.2009.03.008 19403106

32. van Schaik W., Abee T (2005) The role of sigmaB in the stress response of Gram-positive bacteria—targets for food preservation and safety. Curr Opin Biotechnol 16: 218–224. 15831390

33. Horsburgh MJ, Aish JL, White IJ, Shaw L, Lithgow JK et al. (2002) sigmaB modulates virulence determinant expression and stress resistance: characterization of a functional rsbU strain derived from Staphylococcus aureus 8325–4. J Bacteriol 184: 5457–5467. 12218034

34. Chen HY, Chen CC, Fang CS, Hsieh YT, Lin MH et al. (2011) Vancomycin activates sigma(B) in vancomycin-resistant Staphylococcus aureus resulting in the enhancement of cytotoxicity. PLoS ONE 6: e24472. doi: 10.1371/journal.pone.0024472 21912698

35. Mitchell G, Brouillette E, Seguin DL, Asselin AE, Jacob CL et al. (2010) A role for sigma factor B in the emergence of Staphylococcus aureus small-colony variants and elevated biofilm production resulting from an exposure to aminoglycosides. Microb Pathog 48: 18–27. doi: 10.1016/j.micpath.2009.10.003 19825410

36. Bischoff M, Entenza JM, Giachino P (2001) Influence of a functional sigB operon on the global regulators sar and agr in Staphylococcus aureus. J Bacteriol 183: 5171–5179. 11489871

37. Ahmed S, Meghji S, Williams RJ, Henderson B, Brock JH et al. (2001) Staphylococcus aureus fibronectin binding proteins are essential for internalization by osteoblasts but do not account for differences in intracellular levels of bacteria. Infect Immun 69: 2872–2877. 11292701

38. Dunman PM, Murphy E, Haney S, Palacios D, Tucker-Kellogg G et al. (2001) Transcription profiling-based identification of Staphylococcus aureus genes regulated by the agr and/or sarA loci. J Bacteriol 183: 7341–7353. 11717293

39. Gertz S, Engelmann S, Schmid R, Ohlsen K, Hacker J et al. (1999) Regulation of sigmaB-dependent transcription of sigB and asp23 in two different Staphylococcus aureus strains. Mol Gen Genet 261: 558–566. 10323238

40. Giese B, Glowinski F, Paprotka K, Dittmann S, Steiner T et al. (2011) Expression of delta-toxin by Staphylococcus aureus mediates escape from phago-endosomes of human epithelial and endothelial cells in the presence of beta-toxin. Cell Microbiol 13: 316–329. doi: 10.1111/j.1462-5822.2010.01538.x 20946243

41. Lattar SM, Noto LM, Denoel P, Germain S, Buzzola FR et al. (2014) Protein antigens increase the protective efficacy of a capsule-based vaccine against Staphylococcus aureus in a rat model of osteomyelitis. Infect Immun 82: 83–91. doi: 10.1128/IAI.01050-13 24126523

42. Rosenstein R, Götz F (2010) Genomic differences between the food-grade Staphylococcus carnosus and pathogenic staphylococcal species. Int J Med Microbiol 300: 104–108. doi: 10.1016/j.ijmm.2009.08.014 19818681

43. Proctor RA, van Langevelde P., Kristjansson M, Maslow JN, Arbeit RD (1995) Persistent and relapsing infections associated with small-colony variants of Staphylococcus aureus. Clin Infect Dis 20: 95–102. 7727677

44. Abdelnour A, Arvidson S, Bremell T, Ryden C, Tarkowski A (1993) The accessory gene regulator (agr) controls Staphylococcus aureus virulence in a murine arthritis model. Infect Immun 61: 3879–3885. 8359909

45. Gillaspy AF, Hickmon SG, Skinner RA, Thomas JR, Nelson CL et al. (1995) Role of the accessory gene regulator (agr) in pathogenesis of staphylococcal osteomyelitis. Infect Immun 63: 3373–3380. 7642265

46. Nilsson IM, Bremell T, Ryden C, Cheung AL, Tarkowski A (1996) Role of the staphylococcal accessory gene regulator (sar) in septic arthritis. Infect Immun 64: 4438–4443. 8890189

47. Chan PF, Foster SJ (1998) Role of SarA in virulence determinant production and environmental signal transduction in Staphylococcus aureus. J Bacteriol 180: 6232–6241. 9829932

48. Anwar S, Prince LR, Foster SJ, Whyte MK, Sabroe I (2009) The rise and rise of Staphylococcus aureus: laughing in the face of granulocytes. Clin Exp Immunol 157: 216–224. doi: 10.1111/j.1365-2249.2009.03950.x 19604261

49. Zielinska AK, Beenken KE, Joo HS, Mrak LN, Griffin LM et al. (2011) Defining the strain-dependent impact of the Staphylococcal accessory regulator (sarA) on the alpha-toxin phenotype of Staphylococcus aureus. J Bacteriol 193: 2948–2958. doi: 10.1128/JB.01517-10 21478342

50. Herbert S, Ziebandt AK, Ohlsen K, Schafer T, Hecker M et al. (2010) Repair of global regulators in Staphylococcus aureus 8325 and comparative analysis with other clinical isolates. Infect Immun 78: 2877–2889. doi: 10.1128/IAI.00088-10 20212089

51. Jonsson IM, Arvidson S, Foster S, Tarkowski A (2004) Sigma factor B and RsbU are required for virulence in Staphylococcus aureus-induced arthritis and sepsis. Infect Immun 72: 6106–6111. 15385515

52. Lorenz U, Huttinger C, Schafer T, Ziebuhr W, Thiede A et al. (2008) The alternative sigma factor sigma B of Staphylococcus aureus modulates virulence in experimental central venous catheter-related infections. Microbes Infect 10: 217–223. doi: 10.1016/j.micinf.2007.11.006 18328762

53. Depke M, Burian M, Schafer T, Broker BM, Ohlsen K et al. (2012) The alternative sigma factor B modulates virulence gene expression in a murine Staphylococcus aureus infection model but does not influence kidney gene expression pattern of the host. Int J Med Microbiol 302: 33–39. doi: 10.1016/j.ijmm.2011.09.013 22019488

54. Nicholas RO, Li T, McDevitt D, Marra A, Sucoloski S et al. (1999) Isolation and characterization of a sigB deletion mutant of Staphylococcus aureus. Infect Immun 67: 3667–3669. 10377157

55. Pfortner H, Burian MS, Michalik S, Depke M, Hildebrandt P et al. (2014) Activation of the alternative sigma factor SigB of Staphylococcus aureus following internalization by epithelial cells—an in vivo proteomics perspective. Int J Med Microbiol 304: 177–187. doi: 10.1016/j.ijmm.2013.11.014 24480029

56. Jarry TM, Cheung AL (2006) Staphylococcus aureus escapes more efficiently from the phagosome of a cystic fibrosis bronchial epithelial cell line than from its normal counterpart. Infect Immun 74: 2568–2577. 16622192

57. Mestre MB, Fader CM, Sola C, Colombo MI (2010) Alpha-hemolysin is required for the activation of the autophagic pathway in Staphylococcus aureus-infected cells. Autophagy 6: 110–125. 20110774

58. Schnaith A, Kashkar H, Leggio SA, Addicks K, Kronke M et al. (2007) Staphylococcus aureus subvert autophagy for induction of caspase-independent host cell death. J Biol Chem 282: 2695–2706. 17135247

59. Mitchell G, Seguin DL, Asselin AE, Deziel E, Cantin AM et al. (2010) Staphylococcus aureus sigma B-dependent emergence of small-colony variants and biofilm production following exposure to Pseudomonas aeruginosa 4-hydroxy-2-heptylquinoline-N-oxide. BMC Microbiol 10: 33. doi: 10.1186/1471-2180-10-33 20113519

60. Moisan H, Brouillette E, Jacob CL, Langlois-Begin P, Michaud S et al. (2006) Transcription of virulence factors in Staphylococcus aureus small-colony variants isolated from cystic fibrosis patients is influenced by SigB. J Bacteriol 188: 64–76. 16352822

61. Mitchell G, Fugere A, Pepin GK, Brouillette E, Frost EH et al. (2013) SigB is a dominant regulator of virulence in Staphylococcus aureus small-colony variants. PLoS ONE 8: e65018. doi: 10.1371/journal.pone.0065018 23705029

62. Boles BR, Horswill AR (2008) Agr-mediated dispersal of Staphylococcus aureus biofilms. PLoS Pathog 4: e1000052. doi: 10.1371/journal.ppat.1000052 18437240

63. Grundmeier M, Tuchscherr L, Brück M, Viemann D, Roth J et al. (2010) Staphylococcal strains vary greatly in their ability to induce an inflammatory response in endothelial cells. J Infect Dis 201: 871–880. doi: 10.1086/651023 20132035

64. Donegan NP, Cheung AL (2009) Regulation of the mazEF toxin-antitoxin module in Staphylococcus aureus and its impact on sigB expression. J Bacteriol 191: 2795–2805. doi: 10.1128/JB.01713-08 19181798

65. Pane-Farre J, Jonas B, Forstner K, Engelmann S, Hecker M (2006) The sigmaB regulon in Staphylococcus aureus and its regulation. Int J Med Microbiol 296: 237–258. 16644280

66. Bremell T, Abdelnour A, Tarkowski A (1992) Histopathological and serological progression of experimental Staphylococcus aureus arthritis. Infect Immun 60: 2976–2985. 1612762

67. Vandenesch F, Kornblum J, Novick RP (1991) A temporal signal, independent of agr, is required for hla but not spa transcription in Staphylococcus aureus. J Bacteriol 173: 6313–20. 1717437

68. Kullik I, Giachino P, Fuchs T (1998) Deletion of the alternative sigma factor sigmaB in Staphylococcus aureus reveals its function as a global regulator of virulence genes. J Bacteriol 180: 4814–20. 9733682

69. Cheung AL, Ying P (1994) Regulation of alpha- and beta-hemolysins by the sar locus of Staphylococcus aureus. J Bacteriol 176: 580–585. 7507919

70. Giachino P, Engelmann S, Bischoff M (2001) Sigma(B) activity depends on RsbU in Staphylococcus aureus. J Bacteriol 183: 1843–1852. 11222581

71. Bradford MM (1976) A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem 72: 248–254. 942051

72. Madigang MT (2010) Brock Biology of Microorganisms.

73. Cooper MS, Rabbitt EH, Goddard PE, Bartlett WA, Hewison M et al. (2002) Osteoblastic 11beta-hydroxysteroid dehydrogenase type 1 activity increases with age and glucocorticoid exposure. J Bone Miner Res 17: 979–986. 12054173

74. Jaffe EA, Nachman RL, Becker CG, Minick CR (1973) Culture of human endothelial cells derived from umbilical veins. Identification by morphologic and immunologic criteria. J Clin Invest 52: 2745–56. 4355998

75. Mosser DM, Edwards JP (2008) Exploring the full spectrum of macrophage activation. Nat Rev Immunol 8: 958–969. doi: 10.1038/nri2448 19029990

76. Grosz M, Kolter J, Paprotka K, Winkler AC, Schafer D et al. (2014) Cytoplasmic replication of Staphylococcus aureus upon phagosomal escape triggered by phenol-soluble modulin alpha. Cell Microbiol 16: 451–465. doi: 10.1111/cmi.12233 24164701

77. Grundling A, Schneewind O (2007) Synthesis of glycerol phosphate lipoteichoic acid in Staphylococcus aureus. Proc Natl Acad Sci U S A 104: 8478–8483. 17483484

78. Haslinger B, Strangfeld K, Peters G, Schulze-Osthoff K, Sinha B (2003) Staphylococcus aureus alpha-toxin induces apoptosis in peripheral blood mononuclear cells: role of endogenous tumour necrosis factor-alpha and the mitochondrial death pathway. Cell Microbiol 5: 729–41. 12969378

79. Löffler B, Hussain M, Grundmeier M, Bruck M, Holzinger D et al. (2010) Staphylococcus aureus panton-valentine leukocidin is a very potent cytotoxic factor for human neutrophils. PLoS Pathog 6: e1000715. doi: 10.1371/journal.ppat.1000715 20072612

80. Larzabal M, Mercado EC, Vilte DA, Salazar-Gonzalez H, Cataldi A et al. (2010) Designed coiled-coil peptides inhibit the type three secretion system of enteropathogenic Escherichia coli. PLoS ONE 5: e9046. doi: 10.1371/journal.pone.0009046 20140230

81. Garzoni C, Francois P, Huyghe A, Couzinet S, Tapparel C et al. (2007) A global view of Staphylococcus aureus whole genome expression upon internalization in human epithelial cells. BMC Genomics 8: 171. 17570841

82. Hawkins P, Morton DB, Burman O, Dennison N, Honess P et al. (2011) A guide to defining and implementing protocols for the welfare assessment of laboratory animals: eleventh report of the BVAAWF/FRAME/RSPCA/UFAW Joint Working Group on Refinement. Lab Anim 45: 1–13. doi: 10.1258/la.2010.010031 21123303