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Volume 167, Issue 12

Significant variability exists in the cytotoxicity of global methicillin-resistant lineages Open Access

Abstract

is a major human pathogen where the emergence of antibiotic resistant lineages, such as methicillin-resistant (MRSA), is a major health concern. While some MRSA lineages are restricted to the healthcare setting, the epidemiology of MRSA is changing globally, with the rise of specific lineages causing disease in healthy people in the community. In the past two decades, community-associated MRSA (CA-MRSA) has emerged as a clinically important and virulent pathogen associated with serious skin and soft-tissue infections (SSTI). These infections are primarily cytotoxin driven, leading to the suggestion that hypervirulent lineages/multi-locus sequence types (STs) exist. To examine this, we compared the cytotoxicity of 475 MRSA isolates representing five major MRSA STs (ST22, ST93, ST8, ST239 and ST36) by employing a monocyte-macrophage THP-1 cell line as a surrogate for measuring gross cytotoxicity. We demonstrate that while certain MRSA STs contain highly toxic isolates, there is such variability within lineages to suggest that this aspect of virulence should not be inferred from the genotype of any given isolate. Furthermore, by interrogating the accessory gene regulator (Agr) sequences in this collection we identified several Agr mutations that were associated with reduced cytotoxicity. Interestingly, the majority of isolates that were attenuated in cytotoxin production contained no mutations in the locus, indicating a role of other undefined genes in toxin regulation.

  • Received:
  • Accepted:
  • Published Online:
Keyword(s): bacterial pathogenesis , bacterial virulence , cytotoxicity and Staphylococcus aureus
© 2021 The Authors
  • This is an open-access article distributed under the terms of the Creative Commons Attribution License. This article was made open access via a Publish and Read agreement between the Microbiology Society and the corresponding author’s institution.
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2021-12-20
2024-04-19
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References

  1. Gordon RJ, Lowy FD. Pathogenesis of methicillin-resistant Staphylococcus aureus infection. Clin Infect Dis 2008; 46 Suppl 5:S350–9 [View Article] [PubMed]
     [Google Scholar]
  2. Chambers HF, Deleo FR. Waves of resistance: Staphylococcus aureus in the antibiotic era. Nat Rev Microbiol 2009; 7:629–641 [View Article] [PubMed]
     [Google Scholar]
  3. Chambers HF. The changing epidemiology of Staphylococcus aureus?. Emerg Infect Dis 2001; 7:178–182 [View Article] [PubMed]
     [Google Scholar]
  4. David MZ, Daum RS. Community-associated methicillin-resistant Staphylococcus aureus: epidemiology and clinical consequences of an emerging epidemic. Clin Microbiol Rev 2010; 23:616–687 [View Article] [PubMed]
     [Google Scholar]
  5. Spaan AN, Henry T, van Rooijen WJM, Perret M, Badiou C et al. The staphylococcal toxin Panton-Valentine Leukocidin targets human C5a receptors. Cell Host Microbe 2013; 13:584–594 [View Article] [PubMed]
     [Google Scholar]
  6. Diep BA, Chan L, Tattevin P, Kajikawa O, Martin TR et al. Polymorphonuclear leukocytes mediate Staphylococcus aureus Panton-Valentine leukocidin-induced lung inflammation and injury. Proc Natl Acad Sci U S A 2010; 107:5587–5592 [View Article] [PubMed]
     [Google Scholar]
  7. Kobayashi SD, Malachowa N, Whitney AR, Braughton KR, Gardner DJ et al. Comparative analysis of USA300 virulence determinants in a rabbit model of skin and soft tissue infection. J Infect Dis 2011; 204:937–941 [View Article] [PubMed]
     [Google Scholar]
  8. Lipinska U, Hermans K, Meulemans L, Dumitrescu O, Badiou C et al. Panton-Valentine leukocidin does play a role in the early stage of Staphylococcus aureus skin infections: a rabbit model. PLoS One 2011; 6:e22864 [View Article] [PubMed]
     [Google Scholar]
  9. Li M, Diep BA, Villaruz AE, Braughton KR, Jiang X et al. Evolution of virulence in epidemic community-associated methicillin-resistant Staphylococcus aureus. Proc Natl Acad Sci U S A 2009; 106:5883–5888 [View Article] [PubMed]
     [Google Scholar]
  10. Li M, Cheung GYC, Hu J, Wang D, Joo H-S et al. Comparative analysis of virulence and toxin expression of global community-associated methicillin-resistant Staphylococcus aureus strains. J Infect Dis 2010; 202:1866–1876 [View Article] [PubMed]
     [Google Scholar]
  11. Wang R, Braughton KR, Kretschmer D, Bach T-HL, Queck SY et al. Identification of novel cytolytic peptides as key virulence determinants for community-associated MRSA. Nat Med 2007; 13:1510–1514 [View Article] [PubMed]
     [Google Scholar]
  12. Chua KYL, Monk IR, Lin Y-H, Seemann T, Tuck KL et al. Hyperexpression of α-hemolysin explains enhanced virulence of sequence type 93 community-associated methicillin-resistant Staphylococcus aureus . BMC Microbiol 2014; 14:31. [View Article] [PubMed]
     [Google Scholar]
  13. Song L, Hobaugh MR, Shustak C, Cheley S, Bayley H et al. Structure of staphylococcal alpha-hemolysin, a heptameric transmembrane pore. Science 1996; 274:1859–1866 [View Article] [PubMed]
     [Google Scholar]
  14. Berube BJ, Bubeck Wardenburg J. Staphylococcus aureus α-toxin: nearly a century of intrigue. Toxins (Basel) 2013; 5:1140–1166 [View Article] [PubMed]
     [Google Scholar]
  15. Laabei M, Jamieson WD, Yang Y, van den Elsen J, Jenkins ATA. Investigating the lytic activity and structural properties of Staphylococcus aureus phenol soluble modulin (PSM) peptide toxins. Biochim Biophys Acta 2014; 1838:3153–3161 [View Article] [PubMed]
     [Google Scholar]
  16. Novick RP. Autoinduction and signal transduction in the regulation of staphylococcal virulence. Mol Microbiol 2003; 48:1429–1449 [View Article] [PubMed]
     [Google Scholar]
  17. Cheung GYC, Wang R, Khan BA, Sturdevant DE, Otto M. Role of the accessory gene regulator agr in community-associated methicillin-resistant Staphylococcus aureus pathogenesis. Infect Immun 2011; 79:1927–1935 [View Article] [PubMed]
     [Google Scholar]
  18. Laabei M, Recker M, Rudkin JK, Aldeljawi M, Gulay Z et al. Predicting the virulence of MRSA from its genome sequence. Genome Res 2014; 24:839–849 [View Article] [PubMed]
     [Google Scholar]
  19. Wilke GA, Bubeck Wardenburg J. Role of a disintegrin and metalloprotease 10 in Staphylococcus aureus alpha-hemolysin-mediated cellular injury. Proc Natl Acad Sci U S A 2010; 107:13473–13478 [View Article] [PubMed]
     [Google Scholar]
  20. Laabei M, Uhlemann A-C, Lowy FD, Austin ED, Yokoyama M et al. Evolutionary trade-offs underlie the multi-faceted virulence of Staphylococcus aureus . PLoS Biol 2015; 13:e1002229 [View Article] [PubMed]
     [Google Scholar]
  21. Chua K, Seemann T, Harrison PF, Davies JK, Coutts SJ et al. Complete genome sequence of Staphylococcus aureus strain JKD6159, a unique Australian clone of ST93-IV community methicillin-resistant Staphylococcus aureus . J Bacteriol 2010; 192:5556–5557 [View Article] [PubMed]
     [Google Scholar]
  22. Chua KYL, Seemann T, Harrison PF, Monagle S, Korman TM et al. The dominant Australian community-acquired methicillin-resistant Staphylococcus aureus clone ST93-IV [2B] is highly virulent and genetically distinct. PLoS One 2011; 6:e25887 [View Article]
     [Google Scholar]
  23. Harris SR, Feil EJ, Holden MTG, Quail MA, Nickerson EK et al. Evolution of MRSA during hospital transmission and intercontinental spread. Science 2010; 327:469–474 [View Article] [PubMed]
     [Google Scholar]
  24. Recker M, Laabei M, Toleman MS, Reuter S, Saunderson RB et al. Clonal differences in Staphylococcus aureus bacteraemia-associated mortality. Nat Microbiol 2017; 2:1381–1388 [View Article] [PubMed]
     [Google Scholar]
  25. Otto M. Basis of virulence in community-associated methicillin-resistant Staphylococcus aureus . Annu Rev Microbiol 2010; 64:143–162 [View Article] [PubMed]
     [Google Scholar]
  26. Rudkin JK, Edwards AM, Bowden MG, Brown EL, Pozzi C et al. Methicillin resistance reduces the virulence of healthcare-associated methicillin-resistant Staphylococcus aureus by interfering with the agr quorum sensing system. J Infect Dis 2012; 205:798–806 [View Article] [PubMed]
     [Google Scholar]
  27. Nikolskaya AN, Galperin MY. A novel type of conserved DNA-binding domain in the transcriptional regulators of the AlgR/AgrA/LytR family. Nucleic Acids Res 2002; 30:2453–2459 [View Article] [PubMed]
     [Google Scholar]
  28. Koenig RL, Ray JL, Maleki SJ, Smeltzer MS, Hurlburt BK. Staphylococcus aureus AgrA binding to the RNAIII-agr regulatory region. J Bacteriol 2004; 186:7549–7555 [View Article] [PubMed]
     [Google Scholar]
  29. Sidote DJ, Barbieri CM, Wu T, Stock AM. Structure of the Staphylococcus aureus AgrA LytTR domain bound to DNA reveals a beta fold with an unusual mode of binding. Structure 2008; 16:727–735 [View Article] [PubMed]
     [Google Scholar]
  30. Grebe TW, Stock JB. The histidine protein kinase superfamily. Adv Microb Physiol 1999; 41:139–227 [View Article] [PubMed]
     [Google Scholar]
  31. Geisinger E, Muir TW, Novick RP. agr receptor mutants reveal distinct modes of inhibition by staphylococcal autoinducing peptides. Proc Natl Acad Sci U S A 2009; 106:1216–1221 [View Article] [PubMed]
     [Google Scholar]
  32. George Cisar EA, Geisinger E, Muir TW, Novick RP. Symmetric signalling within asymmetric dimers of the Staphylococcus aureus receptor histidine kinase AgrC. Mol Microbiol 2009; 74:44–57 [View Article] [PubMed]
     [Google Scholar]
  33. Hirschman A, Boukhvalova M, VanBruggen R, Wolfe AJ, Stewart RC. Active site mutations in CheA, the signal-transducing protein kinase of the chemotaxis system in Escherichia coli. Biochemistry 2001; 40:13876–13887 [View Article] [PubMed]
     [Google Scholar]
  34. Zhu Y, Inouye M. The role of the G2 box, a conserved motif in the histidine kinase superfamily, in modulating the function of EnvZ. Mol Microbiol 2002; 45:653–663 [View Article] [PubMed]
     [Google Scholar]
  35. Castillo-Ramírez S, Corander J, Marttinen P, Aldeljawi M, Hanage WP et al. Phylogeographic variation in recombination rates within a global clone of methicillin-resistant Staphylococcus aureus . Genome Biol 2012; 13:12 [View Article] [PubMed]
     [Google Scholar]
  36. Sloan TJ, Murray E, Yokoyama M, Massey RC, Chan WC et al. Timing is everything: impact of naturally occurring Staphylococcus aureus AgrC cytoplasmic domain adaptive mutations on autoinduction. J Bacteriol 2019; 201:20 [View Article] [PubMed]
     [Google Scholar]
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Significant variability exists in the cytotoxicity of global methicillin-resistant Staphylococcus aureus lineages
Microbiology 167, 001119 (2021); https://doi.org/10.1099/mic.0.001119
/content/journal/micro/10.1099/mic.0.001119
/content/journal/micro/10.1099/mic.0.001119
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