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Mechanisms of Immune Evasion and Bone Tissue Colonization That Make Staphylococcus aureus the Primary Pathogen in Osteomyelitis

  • Osteoimmunology (M Nakamura and J Lorenzo, Section Editors)
  • Published:
Current Osteoporosis Reports Aims and scope Submit manuscript

Abstract

Purpose of Review

Staphylococcus aureus is the primary pathogen responsible for osteomyelitis, which remains a major healthcare burden. To understand its dominance, here we review the unique pathogenic mechanisms utilized by S. aureus that enable it to cause incurable osteomyelitis.

Recent Findings

Using an arsenal of toxins and virulence proteins, S. aureus kills and usurps immune cells during infection, to produce non-neutralizing pathogenic antibodies that thwart adaptive immunity. S. aureus also has specific mechanisms for distinct biofilm formation on implants, necrotic bone tissue, bone marrow, and within the osteocyte lacuno-canicular networks (OLCN) of live bone. In vitro studies have also demonstrated potential for intracellular colonization of osteocytes, osteoblasts, and osteoclasts.

Summary

S. aureus has evolved a multitude of virulence mechanisms to achieve life-long infection of the bone, most notably colonization of OLCN. Targeting S. aureus proteins involved in these pathways could provide new targets for antibiotics and immunotherapies.

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References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. Tande AJ, Patel R. Prosthetic joint infection. Clin Microbiol Rev. 2014;27(2):302–45. https://doi.org/10.1128/CMR.00111-13.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Bryan AJ, Abdel MP, Sanders TL, Fitzgerald SF, Hanssen AD, Berry DJ. Irrigation and debridement with component retention for acute infection after hip arthroplasty: improved results with contemporary management. J Bone Joint Surg Am. 2017;99(23):2011–8. https://doi.org/10.2106/JBJS.16.01103.

    Article  PubMed  Google Scholar 

  3. Lora-Tamayo J, Murillo O, Iribarren JA, Soriano A, Sanchez-Somolinos M, Baraia-Etxaburu JM, et al. A large multicenter study of methicillin-susceptible and methicillin-resistant Staphylococcus aureus prosthetic joint infections managed with implant retention. Clin Infect Dis. 2013;56(2):182–94. https://doi.org/10.1093/cid/cis746.

    Article  PubMed  Google Scholar 

  4. Nodzo SR, Boyle KK, Spiro S, Nocon AA, Miller AO, Westrich GH. Success rates, characteristics, and costs of articulating antibiotic spacers for total knee periprosthetic joint infection. Knee. 2017;24(5):1175–81. https://doi.org/10.1016/j.knee.2017.05.016.

    Article  PubMed  Google Scholar 

  5. Kurtz SM, Ong KL, Schmier J, Mowat F, Saleh K, Dybvik E, et al. Future clinical and economic impact of revision total hip and knee arthroplasty. J Bone Joint Surg Am. 2007;89(Suppl 3):144–51. https://doi.org/10.2106/JBJS.G.00587.

    Article  PubMed  Google Scholar 

  6. Kurtz S, Ong K, Lau E, Mowat F, Halpern M. Projections of primary and revision hip and knee arthroplasty in the United States from 2005 to 2030. J Bone Joint Surg Am. 2007;89(4):780–5. https://doi.org/10.2106/JBJS.F.00222.

    Article  PubMed  Google Scholar 

  7. • Schwarz EM, Parvizi J, Gehrke T, Aiyer A, Battenberg A, Brown SA, et al. 2018 International Consensus Meeting on Musculoskeletal Infection: Research Priorities from the General Assembly Questions. J Orthop Res. 2019;37(5):997–1006. https://doi.org/10.1002/jor.24293A manuscript outlining important research priorities that were discussed in the 2018 International Consensus Meeting on Musculoskeletal Infection.

    Article  PubMed  Google Scholar 

  8. • Parvizi J, Gehrke T, Mont MA, Callaghan JJ. Introduction: Proceedings of International Consensus on Orthopedic Infections. J Arthroplast. 2019;34(2S):S1–2. https://doi.org/10.1016/j.arth.2018.09.038A manuscript outlining important research priorities that were discussed in the 2018 International Consensus Meeting on Musculoskeletal Infection.

    Article  Google Scholar 

  9. • Saeed K, McLaren AC, Schwarz EM, Antoci V, Arnold WV, Chen AF, et al. 2018 international consensus meeting on musculoskeletal infection: summary from the biofilm workgroup and consensus on biofilm related musculoskeletal infections. J Orthop Res. 2019;37(5):1007–17. https://doi.org/10.1002/jor.24229A manuscript outlining important research priorities that were discussed in the 2018 International Consensus Meeting on Musculoskeletal Infection.

    Article  PubMed  Google Scholar 

  10. Kavanagh N, Ryan EJ, Widaa A, Sexton G, Fennell J, O'Rourke S, et al. Staphylococcal osteomyelitis: disease progression, treatment challenges, and future directions. Clin Microbiol Rev. 2018;31(2). https://doi.org/10.1128/CMR.00084-17.

  11. Lew DP, Waldvogel FA. Osteomyelitis. Lancet. 2004;364(9431):369–79. https://doi.org/10.1016/S0140-6736(04)16727-5.

    Article  CAS  PubMed  Google Scholar 

  12. • Metsemakers WJ, Morgenstern M, McNally MA, Moriarty TF, McFadyen I, Scarborough M, et al. Fracture-related infection: a consensus on definition from an international expert group. Injury. 2018;49(3):505–10. https://doi.org/10.1016/j.injury.2017.08.040A mansucript attempting to solidify the clinical defintion of “fracture-related infection” for the first time based on consensus from an international group of orthopedic surgenons and researchers.

    Article  CAS  PubMed  Google Scholar 

  13. Armstrong DG, Boulton AJM, Bus SA. Diabetic foot ulcers and their recurrence. N Engl J Med. 2017;376(24):2367–75. https://doi.org/10.1056/NEJMra1615439.

    Article  PubMed  Google Scholar 

  14. Gamain R, Coulomb R, Houzir K, Molinari N, Kouyoumdjian P, Lonjon N. Anterior cervical spine surgical site infection and pharyngoesophageal perforation. Ten-year incidence in 1475 patients. Orthop Traumatol Surg Res. 2019;105(4):697–702. https://doi.org/10.1016/j.otsr.2019.02.018.

    Article  PubMed  Google Scholar 

  15. Pulido L, Ghanem E, Joshi A, Purtill JJ, Parvizi J. Periprosthetic joint infection: the incidence, timing, and predisposing factors. Clin Orthop Relat Res. 2008;466(7):1710–5. https://doi.org/10.1007/s11999-008-0209-4.

    Article  PubMed  PubMed Central  Google Scholar 

  16. Metsemakers WJ, Kuehl R, Moriarty TF, Richards RG, Verhofstad MHJ, Borens O, et al. Infection after fracture fixation: current surgical and microbiological concepts. Injury. 2018;49(3):511–22. https://doi.org/10.1016/j.injury.2016.09.019.

    Article  CAS  PubMed  Google Scholar 

  17. Copley LA. Pediatric musculoskeletal infection: trends and antibiotic recommendations. J Am Acad Orthop Surg. 2009;17(10):618–26.

    Article  PubMed  Google Scholar 

  18. Funk SS, Copley LA. Acute hematogenous osteomyelitis in children: pathogenesis, diagnosis, and treatment. Orthop Clin North Am. 2017;48(2):199–208. https://doi.org/10.1016/j.ocl.2016.12.007.

    Article  PubMed  Google Scholar 

  19. Calhoun JH, Manring MM, Shirtliff M. Osteomyelitis of the long bones. Semin Plast Surg. 2009;23(2):59–72. https://doi.org/10.1055/s-0029-1214158.

    Article  PubMed  PubMed Central  Google Scholar 

  20. Kak V, Chandrasekar PH. Bone and joint infections in injection drug users. Infect Dis Clin N Am. 2002;16(3):681–95.

    Article  Google Scholar 

  21. Skolnick P. The opioid epidemic: crisis and solutions. Annu Rev Pharmacol Toxicol. 2018;58:143–59. https://doi.org/10.1146/annurev-pharmtox-010617-052534.

    Article  CAS  PubMed  Google Scholar 

  22. Robbins JM, Strauss G, Aron D, Long J, Kuba J, Kaplan Y. Mortality rates and diabetic foot ulcers: is it time to communicate mortality risk to patients with diabetic foot ulceration? J Am Podiatr Med Assoc. 2008;98(6):489–93.

    Article  PubMed  Google Scholar 

  23. Neville RF, Kayssi A, Buescher T, Stempel MS. The diabetic foot. Curr Probl Surg. 2016;53(9):408–37. https://doi.org/10.1067/j.cpsurg.2016.07.003.

    Article  PubMed  Google Scholar 

  24. Boulton AJ, Vileikyte L, Ragnarson-Tennvall G, Apelqvist J. The global burden of diabetic foot disease. Lancet. 2005;366(9498):1719–24. https://doi.org/10.1016/S0140-6736(05)67698-2.

    Article  PubMed  Google Scholar 

  25. Kaplan SL. Recent lessons for the management of bone and joint infections. J Infect. 2014;68(Suppl 1):S51–6. https://doi.org/10.1016/j.jinf.2013.09.014.

    Article  PubMed  Google Scholar 

  26. Teterycz D, Ferry T, Lew D, Stern R, Assal M, Hoffmeyer P, et al. Outcome of orthopedic implant infections due to different staphylococci. Int J Infect Dis. 2010;14(10):e913–8. https://doi.org/10.1016/j.ijid.2010.05.014.

    Article  PubMed  Google Scholar 

  27. Ogston A. Report upon micro-organisms in surgical diseases. Br Med J. 1881;1(1054):369 b2–75.

    Article  Google Scholar 

  28. Hemmady MV, Al-Maiyah M, Shoaib A, Morgan-Jones RL. Recurrence of chronic osteomyelitis in a regenerated fibula after 65 years. Orthopedics. 2007;30(5).

    Article  PubMed  Google Scholar 

  29. Gallie W. First recurrence of osteomyelitis eighty years after infection. J Bone Jt Surg British volume. 1951;33(1):110–1.

    Article  Google Scholar 

  30. Bosse MJ, Gruber HE, Ramp WK. Internalization of bacteria by osteoblasts in a patient with recurrent, long-term osteomyelitis: a case report. JBJS. 2005;87(6):1343–7.

    Article  Google Scholar 

  31. Libraty DH, Patkar C, Torres B. Staphylococcus aureus reactivation osteomyelitis after 75 years. N Engl J Med. 2012;366(5):481–2.

    Article  CAS  PubMed  Google Scholar 

  32. •• Broker BM, Mrochen D, Peton V. The T cell response to Staphylococcus aureus. pathogens. 2016;5(1). https://doi.org/10.3390/pathogens5010031An excellent review that summarizesS.aureus-specific T cell response in disease and colonization.

    Article  PubMed Central  CAS  Google Scholar 

  33. O'Brien EC, McLoughlin RM. Considering the ‘alternatives’ for next-generation anti-Staphylococcus aureus vaccine development. Trends Mol Med. 2019;25(3):171–84. https://doi.org/10.1016/j.molmed.2018.12.010.

    Article  CAS  PubMed  Google Scholar 

  34. Seebach E, Kubatzky KF. Chronic implant-related bone infections—can immune modulation be a therapeutic strategy? Front Immunol. 2019;10(1724). https://doi.org/10.3389/fimmu.2019.01724.

  35. Moks T, Abrahmsen L, Nilsson B, Hellman U, Sjoquist J, Uhlen M. Staphylococcal protein A consists of five IgG-binding domains. Eur J Biochem. 1986;156(3):637–43.

    Article  CAS  PubMed  Google Scholar 

  36. Cedergren L, Andersson R, Jansson B, Uhlen M, Nilsson B. Mutational analysis of the interaction between staphylococcal protein A and human IgG1. Protein Eng. 1993;6(4):441–8.

    Article  CAS  PubMed  Google Scholar 

  37. Schneewind O, Model P, Fischetti VA. Sorting of protein A to the staphylococcal cell wall. Cell. 1992;70(2):267–81. https://doi.org/10.1016/0092-8674(92)90101-h.

    Article  CAS  PubMed  Google Scholar 

  38. Graille M, Stura EA, Corper AL, Sutton BJ, Taussig MJ, Charbonnier JB, et al. Crystal structure of a Staphylococcus aureus protein A domain complexed with the Fab fragment of a human IgM antibody: structural basis for recognition of B-cell receptors and superantigen activity. Proc Natl Acad Sci U S A. 2000;97(10):5399–404. https://doi.org/10.1073/pnas.97.10.5399.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Goodyear CS, Silverman GJ. Death by a B cell superantigen: in vivo VH-targeted apoptotic supraclonal B cell deletion by a Staphylococcal toxin. J Exp Med. 2003;197(9):1125–39. https://doi.org/10.1084/jem.20020552.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Pauli NT, Kim HK, Falugi F, Huang M, Dulac J, Henry Dunand C, et al. Staphylococcus aureus infection induces protein A-mediated immune evasion in humans. J Exp Med. 2014;211(12):2331–9. https://doi.org/10.1084/jem.20141404.

    Article  PubMed  PubMed Central  Google Scholar 

  41. Keener AB, Thurlow LT, Kang S, Spidale NA, Clarke SH, Cunnion KM, et al. Staphylococcus aureus protein A disrupts immunity mediated by long-lived plasma cells. J Immunol. 2017;198(3):1263–73. https://doi.org/10.4049/jimmunol.1600093.

    Article  CAS  PubMed  Google Scholar 

  42. • Falugi F, Kim HK, Missiakas DM, Schneewind O. Role of protein A in the evasion of host adaptive immune responses by Staphylococcus aureus. mBio. 2013;4(5):e00575–13. https://doi.org/10.1128/mBio.00575-13This study describes the key role of protein A in the pathogenesis of staphylococcal infections.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Kim HK, Cheng AG, Kim HY, Missiakas DM, Schneewind O. Nontoxigenic protein A vaccine for methicillin-resistant Staphylococcus aureus infections in mice. J Exp Med. 2010;207(9):1863–70. https://doi.org/10.1084/jem.20092514.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Thammavongsa V, Rauch S, Kim HK, Missiakas DM, Schneewind O. Protein A-neutralizing monoclonal antibody protects neonatal mice against Staphylococcus aureus. Vaccine. 2015;33(4):523–6. https://doi.org/10.1016/j.vaccine.2014.11.051.

    Article  CAS  PubMed  Google Scholar 

  45. Kim HK, Falugi F, Thomer L, Missiakas DM, Schneewind O. Protein A suppresses immune responses during Staphylococcus aureus bloodstream infection in guinea pigs. mBio. 2015;6(1). https://doi.org/10.1128/mBio.02369-14.

  46. Chen X, Sun Y, Missiakas D, Schneewind O. Staphylococcus aureus decolonization of mice with monoclonal antibody neutralizing protein A. J Infect Dis. 2019;219(6):884–8. https://doi.org/10.1093/infdis/jiy597.

    Article  PubMed  Google Scholar 

  47. Nygaard TK, Kobayashi SD, Freedman B, Porter AR, Voyich JM, Otto M, et al. Interaction of staphylococci with human B cells. PLoS One. 2016;11(10):e0164410. https://doi.org/10.1371/journal.pone.0164410.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Garcia BL, Ramyar KX, Ricklin D, Lambris JD, Geisbrecht BV. Advances in understanding the structure, function, and mechanism of the SCIN and Efb families of staphylococcal immune evasion proteins. Adv Exp Med Biol. 2012;946:113–33. https://doi.org/10.1007/978-1-4614-0106-3_7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. •• Nishitani K, Beck CA, Rosenberg AF, Kates SL, Schwarz EM, Daiss JL. A diagnostic serum antibody test for patients with Staphylococcus aureus osteomyelitis. Clin Orthop Relat Res. 2015;473(9):2735–49. https://doi.org/10.1007/s11999-015-4354-2The first Luminex-based immunoassay in blood serum to detectS.aureusosteomyelitis in patients.

    Article  PubMed  PubMed Central  Google Scholar 

  50. Holtfreter S, Kolata J, Broker BM. Towards the immune proteome of Staphylococcus aureus—the anti-S. aureus antibody response. Int J Med Microbiol. 2010;300(2-3):176–92. https://doi.org/10.1016/j.ijmm.2009.10.002.

    Article  CAS  PubMed  Google Scholar 

  51. van Belkum A, Melles DC, Nouwen J, van Leeuwen WB, van Wamel W, Vos MC, et al. Co-evolutionary aspects of human colonisation and infection by Staphylococcus aureus. Infect Genet Evol. 2009;9(1):32–47.

    Article  PubMed  CAS  Google Scholar 

  52. Stentzel S, Sundaramoorthy N, Michalik S, Nordengrun M, Schulz S, Kolata J, et al. Specific serum IgG at diagnosis of Staphylococcus aureus bloodstream invasion is correlated with disease progression. J Proteome. 2015;128:1–7. https://doi.org/10.1016/j.jprot.2015.06.018.

    Article  CAS  Google Scholar 

  53. Verkaik NJ, Boelens HA, de Vogel CP, Tavakol M, Bode LG, Verbrugh HA, et al. Heterogeneity of the humoral immune response following Staphylococcus aureus bacteremia. Eur J Clin Microbiol Infect Dis. 2010;29(5):509–18. https://doi.org/10.1007/s10096-010-0888-0.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. den Reijer PM, Lemmens-den Toom N, Kant S, Snijders SV, Boelens H, Tavakol M, et al. Characterization of the humoral immune response during Staphylococcus aureus bacteremia and global gene expression by Staphylococcus aureus in human blood. PLoS One. 2013;8(1):e53391. https://doi.org/10.1371/journal.pone.0053391.

    Article  CAS  Google Scholar 

  55. Gedbjerg N, LaRosa R, Hunter JG, Varrone JJ, Kates SL, Schwarz EM, et al. Anti-glucosaminidase IgG in sera as a biomarker of host immunity against Staphylococcus aureus in orthopaedic surgery patients. J Bone Joint Surg Am. 2013;95(22):e171. https://doi.org/10.2106/JBJS.L.01654.

    Article  PubMed  PubMed Central  Google Scholar 

  56. Fowler VG, Allen KB, Moreira ED, Moustafa M, Isgro F, Boucher HW, et al. Effect of an investigational vaccine for preventing Staphylococcus aureus infections after cardiothoracic surgery: a randomized trial. JAMA. 2013;309(13):1368–78. https://doi.org/10.1001/jama.2013.3010.

    Article  CAS  PubMed  Google Scholar 

  57. Varrone JJ, Li D, Daiss JL, Schwarz EM. Anti-glucosaminidase monoclonal antibodies as a passive immunization for methicillin-resistant Staphylococcus aureus (MRSA) orthopaedic infections. Bonekey Osteovision. 2011;8:187–94. https://doi.org/10.1138/20110506.

    Article  PubMed  PubMed Central  Google Scholar 

  58. • Varrone JJ, de Mesy Bentley KL, Bello-Irizarry SN, Nishitani K, Mack S, Hunter JG, et al. Passive immunization with anti-glucosaminidase monoclonal antibodies protects mice from implant-associated osteomyelitis by mediating opsonophagocytosis of Staphylococcus aureus megaclusters. J Orthop Res. 2014;32(10):1389–96. https://doi.org/10.1002/jor.22672.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Ghasemzadeh-Moghaddam H, van Wamel W, van Belkum A, Hamat RA, Tavakol M, Neela VK. Humoral immune consequences of Staphylococcus aureus ST239-associated bacteremia. Eur J Clin Microbiol Infect Dis. 2018;37(2):255–63. https://doi.org/10.1007/s10096-017-3124-3.

    Article  CAS  PubMed  Google Scholar 

  60. Wu Y, Liu X, Akhgar A, Li JJ, Mok H, Sellman BR, et al. Prevalence of IgG and neutralizing antibodies against Staphylococcus aureus alpha-toxin in healthy human subjects and diverse patient populations. Infect Immun. 2018;86(3). https://doi.org/10.1128/IAI.00671-17.

  61. Rigat F, Bartolini E, Dalsass M, Kumar N, Marchi S, Speziale P, et al. Retrospective identification of a broad IgG repertoire differentiating patients with S. aureus skin and soft tissue infections from controls. Front Immunol. 2019;10:114. https://doi.org/10.3389/fimmu.2019.00114.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. • Carter MJ, Mitchell RM, Meyer Sauteur PM, Kelly DF, Truck J. The antibody-secreting cell response to infection: kinetics and clinical applications. Front Immunol. 2017;8:630. https://doi.org/10.3389/fimmu.2017.00630An excellent review on antibody-secreting cell reponse to infection.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Lee FE, Falsey AR, Halliley JL, Sanz I, Walsh EE. Circulating antibody-secreting cells during acute respiratory syncytial virus infection in adults. J Infect Dis. 2010;202(11):1659–66. https://doi.org/10.1086/657158.

    Article  PubMed  Google Scholar 

  64. Lee FE, Halliley JL, Walsh EE, Moscatiello AP, Kmush BL, Falsey AR, et al. Circulating human antibody-secreting cells during vaccinations and respiratory viral infections are characterized by high specificity and lack of bystander effect. J Immunol. 2011;186(9):5514–21. https://doi.org/10.4049/jimmunol.1002932.

    Article  CAS  PubMed  Google Scholar 

  65. Radke EE, Brown SM, Pelzek AJ, Fulmer Y, Hernandez DN, Torres VJ, et al. Hierarchy of human IgG recognition within the Staphylococcus aureus immunome. Sci Rep. 2018;8(1):13296. https://doi.org/10.1038/s41598-018-31424-3.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Raqib R, Mondal D, Karim MA, Chowdhury F, Ahmed S, Luby S, et al. Detection of antibodies secreted from circulating Mycobacterium tuberculosis-specific plasma cells in the diagnosis of pediatric tuberculosis. Clin Vaccine Immunol. 2009;16(4):521–7. https://doi.org/10.1128/CVI.00391-08.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Kyu SY, Kobie J, Yang H, Zand MS, Topham DJ, Quataert SA, et al. Frequencies of human influenza-specific antibody secreting cells or plasmablasts post vaccination from fresh and frozen peripheral blood mononuclear cells. J Immunol Methods. 2009;340(1):42–7. https://doi.org/10.1016/j.jim.2008.09.025.

    Article  CAS  PubMed  Google Scholar 

  68. •• Oh I, Muthukrishnan G, Ninomiya MJ, Brodell JD Jr, Smith BL, Lee CC, et al. Tracking anti-Staphylococcus aureus antibodies produced in vivo and ex vivo during foot salvage therapy for diabetic foot infections reveals prognostic insights and evidence of diversified humoral immunity. Infect Immun. 2018;86(12). https://doi.org/10.1128/IAI.00629-18The first study to describe the utility of antibodies secreted by circulating plasmablasts as a diagnostic and prognostic tool to identifyS.aureusdiabetic foot infections.

  69. Cheng AG, DeDent AC, Schneewind O, Missiakas D. A play in four acts: Staphylococcus aureus abscess formation. Trends Microbiol. 2011;19(5):225–32.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. McDevitt D, Francois P, Vaudaux P, Foster T. Molecular characterization of the clumping factor (fibrinogen receptor) of Staphylococcus aureus. Mol Microbiol. 1994;11(2):237–48.

    Article  CAS  PubMed  Google Scholar 

  71. Higgins J, Loughman A, Van Kessel KP, Van Strijp JA, Foster TJ. Clumping factor A of Staphylococcus aureus inhibits phagocytosis by human polymorphonuclear leucocytes. FEMS Microbiol Lett. 2006;258(2):290–6.

    Article  CAS  PubMed  Google Scholar 

  72. Postma B, Poppelier MJ, Van Galen JC, Prossnitz ER, Van Strijp JA, De Haas CJ, et al. Chemotaxis inhibitory protein of Staphylococcus aureus binds specifically to the C5a and formylated peptide receptor. J Immunol. 2004;172(11):6994–7001.

    Article  CAS  PubMed  Google Scholar 

  73. Rooijakkers SH, Ruyken M, Van Roon J, Van Kessel KP, Van Strijp JA, Van Wamel WJ. Early expression of SCIN and CHIPS drives instant immune evasion by Staphylococcus aureus. Cell Microbiol. 2006;8(8):1282–93.

    Article  CAS  PubMed  Google Scholar 

  74. Hammer ND, Skaar EP. Molecular mechanisms of Staphylococcus aureus iron acquisition. Annu Rev Microbiol. 2011;65:129–47.

    Article  CAS  PubMed  Google Scholar 

  75. Kim HK, DeDent A, Cheng AG, McAdow M, Bagnoli F, Missiakas DM, et al. IsdA and IsdB antibodies protect mice against Staphylococcus aureus abscess formation and lethal challenge. Vaccine. 2010;28(38):6382–92.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Cheng AG, Kim HK, Burts ML, Krausz T, Schneewind O, Missiakas DM. Genetic requirements for Staphylococcus aureus abscess formation and persistence in host tissues. FASEB J. 2009;23(10):3393–404.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Viana D, Blanco J, Tormo-Más MÁ, Selva L, Guinane CM, Baselga R, et al. Adaptation of Staphylococcus aureus to ruminant and equine hosts involves SaPI-carried variants of von Willebrand factor-binding protein. Mol Microbiol. 2010;77(6):1583–94.

    Article  CAS  PubMed  Google Scholar 

  78. Burts ML, DeDent AC, Missiakas DM. EsaC substrate for the ESAT-6 secretion pathway and its role in persistent infections of Staphylococcus aureus. Mol Microbiol. 2008;69(3):736–46.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. • Masters EA, Trombetta RP, de Mesy Bentley KL, Boyce BF, Gill AL, Gill SR, et al. Evolving concepts in bone infection: redefining “biofilm”, “acute vs. chronic osteomyelitis”, “the immune proteome” and “local antibiotic therapy”. Bone Research. 2019;7(1):20. https://doi.org/10.1038/s41413-019-0061-zA great review summarizing recent advances related to bone infection and antibiotic therpaeutic strategies to tackle osteomyelitis.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Farnsworth CW, Schott EM, Jensen SE, Zukoski J, Benvie AM, Refaai MA, et al. Adaptive upregulation of clumping factor A (ClfA) by S. aureus in the obese, type 2 diabetic host mediates increased virulence. Infect Immun. 2017; IAI. 01005-16.

  81. Cassat JE, Hammer ND, Campbell JP, Benson MA, Perrien DS, Mrak LN, et al. A secreted bacterial protease tailors the Staphylococcus aureus virulence repertoire to modulate bone remodeling during osteomyelitis. Cell Host Microbe. 2013;13(6):759–72.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Scherr TD, Heim CE, Morrison JM, Kielian T. Hiding in plain sight: interplay between staphylococcal biofilms and host immunity. Front Immunol. 2014;5:37.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  83. Stoodley P, Nistico L, Johnson S, Lasko L-A, Baratz M, Gahlot V, et al. Direct demonstration of viable Staphylococcus aureus biofilms in an infected total joint arthroplasty: a case report. J Bone Joint Surg Am. 2008;90(8):1751.

    Article  PubMed  PubMed Central  Google Scholar 

  84. Flemming H-C, Wingender J. The biofilm matrix. Nat Rev Microbiol. 2010;8(9):623–33.

    Article  CAS  PubMed  Google Scholar 

  85. Mah T-FC, O’Toole GA. Mechanisms of biofilm resistance to antimicrobial agents. Trends Microbiol. 2001;9(1):34–9.

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  87. Sendi P, Rohrbach M, Graber P, Frei R, Ochsner PE, Zimmerli W. Staphylococcus aureus small colony variants in prosthetic joint infection. Clin Infect Dis. 2006;43(8):961–7.

    Article  PubMed  Google Scholar 

  88. Gillaspy AF, Hickmon SG, Skinner RA, Thomas JR, Nelson CL, Smeltzer MS. Role of the accessory gene regulator (agr) in pathogenesis of staphylococcal osteomyelitis. Infect Immun. 1995;63(9):3373–80.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Salam AM, Quave CL. Targeting virulence in Staphylococcus aureus by chemical inhibition of the accessory gene regulator system in vivo. MSphere. 2018;3(1):e00500–17.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Ricciardi BF, Muthukrishnan G, Masters E, Ninomiya M, Lee CC, Schwarz EM. Staphylococcus aureus evasion of host immunity in the setting of prosthetic joint infection: biofilm and beyond. Curr Rev Musculoskelet Med. 2018. https://doi.org/10.1007/s12178-018-9501-4.

    Article  PubMed  PubMed Central  Google Scholar 

  91. Paharik AE, Horswill AR. The Staphylococcal biofilm: adhesins, regulation, and host response. Microbiol Spectr. 2016;4(2). https://doi.org/10.1128/microbiolspec.VMBF-0022-2015.

  92. Whiteley M, Bangera MG, Bumgarner RE, Parsek MR, Teitzel GM, Lory S, et al. Gene expression in Pseudomonas aeruginosa biofilms. Nature. 2001;413(6858):860–4.

    Article  CAS  PubMed  Google Scholar 

  93. Werner E, Roe F, Bugnicourt A, Franklin MJ, Heydorn A, Molin S, et al. Stratified growth in Pseudomonas aeruginosa biofilms. Appl Environ Microbiol. 2004;70(10):6188–96.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Deligianni E, Pattison S, Berrar D, Ternan NG, Haylock RW, Moore JE, et al. Pseudomonas aeruginosa cystic fibrosis isolates of similar RAPD genotype exhibit diversity in biofilm forming ability in vitro. BMC Microbiol. 2010;10(1):38.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  95. Ceri H, Olson M, Stremick C, Read R, Morck D, Buret A. The Calgary Biofilm Device: new technology for rapid determination of antibiotic susceptibilities of bacterial biofilms. J Clin Microbiol. 1999;37(6):1771–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Yang L, Haagensen JA, Jelsbak L, Johansen HK, Sternberg C, Høiby N, et al. In situ growth rates and biofilm development of Pseudomonas aeruginosa populations in chronic lung infections. J Bacteriol. 2008;190(8):2767–76.

    Article  CAS  PubMed  Google Scholar 

  97. Reizner W, Hunter J, O’Malley N, Southgate R, Schwarz E, Kates S. A systematic review of animal models for Staphylococcus aureus osteomyelitis. Eur Cells Mater. 2014;27:196.

    Article  CAS  Google Scholar 

  98. Nishitani K, Sutipornpalangkul W, de Mesy Bentley KL, Varrone JJ, Bello-Irizarry SN, Ito H, et al. Quantifying the natural history of biofilm formation in vivo during the establishment of chronic implant-associated Staphylococcus aureus osteomyelitis in mice to identify critical pathogen and host factors. J Orthop Res. 2015;33(9):1311–9.

    Article  PubMed  PubMed Central  Google Scholar 

  99. Burger EH, Klein-Nulend J. Mechanotransduction in bone—role of the lacuno-canalicular network. FASEB J. 1999;13(9001):S101–S12.

    Article  CAS  PubMed  Google Scholar 

  100. •• de Mesy Bentley KL, Trombetta R, Nishitani K, Bello-Irizarry SN, Ninomiya M, Zhang L, et al. Evidence of Staphylococcus aureus deformation, proliferation, and migration in canaliculi of live cortical bone in murine models of osteomyelitis. J Bone Miner Res. 2017;32(5):985–90. https://doi.org/10.1002/jbmr.3055Murine and human in vivo evidence demonstrating thatS.aureuscan enter and prolierate in the submicron canilicular space deep within the bone.

    Article  CAS  PubMed  Google Scholar 

  101. •• de Mesy Bentley KL, MacDonald A, Schwarz EM, Oh I. Chronic osteomyelitis with Staphylococcus aureus deformation in submicron canaliculi of osteocytes: a case report. JBJS Case Connect. 2018. https://doi.org/10.2106/JBJS.CC.17.00154Murine and human in vivo evidence demonstrating thatS.aureuscan enter and prolierate in the submicron canilicular space deep within the bone.

    Article  PubMed  PubMed Central  Google Scholar 

  102. Elysia A, Masters ATS, Begolo S, Luke EN, Barrett SC, Overby CT, et al. An in vitro platform for elucidating the molecular genetics of S. aureus invasion of the osteocyte lacuno-canalicular network during chronic osteomyelitis Nanomedicine. Nanotechnol Biol Med. 2019. https://doi.org/10.1016/j.nano.2019.102039.

    Article  CAS  Google Scholar 

  103. Malouin F, Brouillette E, Martinez A, Boyll BJ, Toth JL, Gage JL, et al. Identification of antimicrobial compounds active against intracellular Staphylococcus aureus. FEMS Immunol Med Microbiol. 2005;45(2):245–52.

    Article  CAS  PubMed  Google Scholar 

  104. Vesga O, Groeschel MC, Otten MF, Brar DW, Vann JM, Proctor RA. Staphylococcus aureus small colony variants are induced by the endothelial cell intracellular milieu. J Infect Dis. 1996;173(3):739–42.

    Article  CAS  PubMed  Google Scholar 

  105. Krut O, Sommer H, Krönke M. Antibiotic-induced persistence of cytotoxic Staphylococcus aureus in non-phagocytic cells. J Antimicrob Chemother. 2004;53(2):167–73.

    Article  CAS  PubMed  Google Scholar 

  106. Edwards AM, Potts JR, Josefsson E, Massey RC. Staphylococcus aureus host cell invasion and virulence in sepsis is facilitated by the multiple repeats within FnBPA. PLoS Pathog. 2010;6(6):e1000964.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  107. Garzoni C, Kelley WL. Staphylococcus aureus: new evidence for intracellular persistence. Trends Microbiol. 2009;17(2):59–65.

    Article  CAS  PubMed  Google Scholar 

  108. Reott MA Jr, Ritchie-Miller SL, Anguita J, Hudson MC. TRAIL expression is induced in both osteoblasts containing intracellular Staphylococcus aureus and uninfected osteoblasts in infected cultures. FEMS Microbiol Lett. 2008;278(2):185–92.

    Article  CAS  PubMed  Google Scholar 

  109. Mohamed W, Sommer U, Sethi S, Domann E, Thormann U, Schutz I, et al. Intracellular proliferation of S. aureus in osteoblasts and effects of rifampicin and gentamicin on S. aureus intracellular proliferation and survival. Eur Cell Mater. 2014;28:258–68.

    Article  CAS  PubMed  Google Scholar 

  110. Ellington JK, Elhofy A, Bost KL, Hudson MC. Involvement of mitogen-activated protein kinase pathways in Staphylococcus aureus invasion of normal osteoblasts. Infect Immun. 2001;69(9):5235–42.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Klenerman L. A history of osteomyelitis from the Journal of Bone and Joint Surgery: 1948 to 2006. J Bone Jt Surg British volume. 2007;89(5):667–70.

    Article  CAS  Google Scholar 

  112. Yang D, Wijenayaka AR, Solomon LB, Pederson SM, Findlay DM, Kidd SP, et al. Novel insights into Staphylococcus aureus deep bone infections: the involvement of osteocytes. mBio. 2018;9(2):e00415–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Tuchscherr L, Heitmann V, Hussain M, Viemann D, Roth J, von Eiff C, et al. Staphylococcus aureus small-colony variants are adapted phenotypes for intracellular persistence. J Infect Dis. 2010;202(7):1031–40.

    Article  PubMed  Google Scholar 

  114. Reilly S, Hudson M, Kellam J, Ramp W. In vivo internalization of Staphylococcus aureus by embryonic chick osteoblasts. Bone. 2000;26(1):63–70.

    Article  CAS  PubMed  Google Scholar 

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Funding

GM is supported by grants from National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) P30 AR069655 pilot and AO Trauma Research Fellowship (Davos, Switzerland). EMS is supported by grants from NIAMS P50 AR072000, P30 AR069655) and AOTrauma, Clinical Priority Program (Davos, Switzerland). JLD is supported by grants from the National Institute of Allergy and Infectious Diseases (NIAID) R21 AI119646.

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Correspondence to Edward M. Schwarz.

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Gowrishankar Muthukrishnan reports grants from AOTrauma Research Fellowship, during the conduct of the study. John Daiss reports grants from NIH NIAID and is the cofounder of Micro B-Plex and works there part-time, during the conduct of the study. Edward Schwarz reports grants from AO Trauma and is the founder of Telephus Medical LLC. Dr. Daiss and Dr. Schwarz also have a patent (antibody-based diagnostics of S. aureus osteomyelitis) pending.

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Muthukrishnan, G., Masters, E.A., Daiss, J.L. et al. Mechanisms of Immune Evasion and Bone Tissue Colonization That Make Staphylococcus aureus the Primary Pathogen in Osteomyelitis. Curr Osteoporos Rep 17, 395–404 (2019). https://doi.org/10.1007/s11914-019-00548-4

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