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Volume 73, Issue 4

CXCR2 perturbation promotes implant-associated infection Open Access

Abstract

is the leading cause of acute medical implant infections, representing a significant modern medical concern. The success of as a pathogen in these cases resides in its arsenal of virulence factors, resistance to multiple antimicrobials, mechanisms of immune modulation, and ability to rapidly form biofilms associated with implant surfaces. device-associated, biofilm-mediated infections are often persistent and notoriously difficult to treat, skewing innate immune responses to promote chronic reoccurring infections. While relatively little is known of the role neutrophils play in response to acute biofilm infections, these effector cells must be efficiently recruited to sites of infection via directed chemotaxis. Here we investigate the effects of modulating CXC chemokine receptor 2 (CXCR2) activity, predominantly expressed on neutrophils, during implant-associated infection.

We hypothesize that modulation of CXCR2 expression and/or signalling activities during infection, and thus neutrophil recruitment, extravasation and antimicrobial activity, will affect infection control and bacterial burdens in a mouse model of implant-associated infection.

This investigation aims to elucidate the impact of altered CXCR2 activity during biofilm-mediated infection that may help develop a framework for an effective novel strategy to prevent morbidity and mortality associated with implant infections.

To examine the role of CXCR2 during implant infection, we employed a mouse model of indwelling subcutaneous catheter infection using a community-associated methicillin-resistant (MRSA) strain. To assess the role of CXCR2 induction or inhibition during infection, treatment groups received daily intraperitoneal doses of either Lipocalin-2 (Lcn2) or AZD5069, respectively. At the end of the study, catheters and surrounding soft tissues were analysed for bacterial burdens and dissemination, and transcription within the implant-associated tissues was quantified.

Mice treated with Lcn2 developed higher bacterial burdens within the soft tissue surrounding the implant site, which was associated with increased expression. AZD5069 treatment also resulted in increased implant- and tissues-associated bacterial titres, as well as enhanced expression.

Our results demonstrate that CXCR2 plays an essential role in regulating the severity of implant-associated infections. Interestingly, however, perturbation of CXCR2 expression or signalling both resulted in enhanced transcription and elevated implant-associated bacterial burdens. Thus, CXCR2 appears finely tuned to efficiently recruit effector cells and mediate control of biofilm-mediated infection.

  • Received:
  • Accepted:
  • Published Online:
Keyword(s): biofilm , CXCR2 , neutrophil and Staphylococcus aureus
Funding
This study was supported by the:
  • National Heart, Lung, and Blood Institute (Award R01HL158926)
    • Principle Award Recipient: TaraM. Nordgren
  • College of Veterinary Medicine and Biomedical Sciences, Colorado State University
    • Principle Award Recipient: CaseyGries
© 2024 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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2024-04-03
2024-04-30
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References

  1. Tong SYC, Davis JS, Eichenberger E, Holland TL, Fowler VG. Staphylococcus aureus infections: epidemiology, pathophysiology, clinical manifestations, and management. Clin Microbiol Rev 2015; 28:603–661 [View Article] [PubMed]
     [Google Scholar]
  2. Rosman CWK, van Dijl JM, Sjollema J. Interactions between the foreign body reaction and Staphylococcus aureus biomaterial-associated infection. Winning strategies in the derby on biomaterial implant surfaces. Crit Rev Microbiol 2022; 48:624–640 [View Article] [PubMed]
     [Google Scholar]
  3. Gries CM, Biddle T, Bose JL, Kielian T, Lo DD. Staphylococcus aureus fibronectin binding protein a mediates biofilm development and infection. Infect Immun 2020; 88:e00859-19 [View Article] [PubMed]
     [Google Scholar]
  4. Gries CM, Kielian T. Staphylococcal biofilms and immune polarization during prosthetic joint infection. J Am Acad Orthop Surg 2017; 25 Suppl 1:S20–S24 [View Article] [PubMed]
     [Google Scholar]
  5. Rosales C. Neutrophils at the crossroads of innate and adaptive immunity. J Leukoc Biol 2020; 108:377–396 [View Article] [PubMed]
     [Google Scholar]
  6. de Oliveira S, Rosowski EE, Huttenlocher A. Neutrophil migration in infection and wound repair: going forward in reverse. Nat Rev Immunol 2016; 16:378–391 [View Article] [PubMed]
     [Google Scholar]
  7. Eisele NA, Lee-Lewis H, Besch-Williford C, Brown CR, Anderson DM. Chemokine receptor CXCR2 mediates bacterial clearance rather than neutrophil recruitment in a murine model of pneumonic plague. Am J Pathol 2011; 178:1190–1200 [View Article] [PubMed]
     [Google Scholar]
  8. Tsai WC, Strieter RM, Mehrad B, Newstead MW, Zeng X et al. CXC chemokine receptor CXCR2 is essential for protective innate host response in murine Pseudomonas aeruginosa pneumonia. Infect Immun 2000; 68:4289–4296 [View Article] [PubMed]
     [Google Scholar]
  9. Boff D, Oliveira VLS, Queiroz Junior CM, Silva TA, Allegretti M et al. CXCR2 is critical for bacterial control and development of joint damage and pain in Staphylococcus aureus-induced septic arthritis in mouse. Eur J Immunol 2018; 48:454–463 [View Article] [PubMed]
     [Google Scholar]
  10. Olszyna DP, Florquin S, Sewnath M, Branger J, Speelman P et al. CXC chemokine receptor 2 contributes to host defense in murine urinary tract infection. J Infect Dis 2001; 184:301–307 [View Article] [PubMed]
     [Google Scholar]
  11. Paudel S, Baral P, Ghimire L, Bergeron S, Jin L et al. CXCL1 regulates neutrophil homeostasis in pneumonia-derived sepsis caused by Streptococcus pneumoniae serotype 3. Blood 2019; 133:1335–1345 [View Article] [PubMed]
     [Google Scholar]
  12. Bhattacharya M, Berends ETM, Chan R, Schwab E, Roy S et al. Staphylococcus aureus biofilms release leukocidins to elicit extracellular trap formation and evade neutrophil-mediated killing. Proc Natl Acad Sci U S A 2018; 115:7416–7421 [View Article] [PubMed]
     [Google Scholar]
  13. Koymans KJ, Bisschop A, Vughs MM, van Kessel KPM, de Haas CJC et al. Staphylococcal superantigen-like protein 1 and 5 (SSL1 & SSL5) limit neutrophil chemotaxis and migration through MMP-inhibition. Int J Mol Sci 2016; 17:1072 [View Article] [PubMed]
     [Google Scholar]
  14. Gries CM, Rivas Z, Chen J, Lo DD. Intravital multiphoton examination of implant-associated Staphylococcus aureus biofilm infection. Front Cell Infect Microbiol 2020; 10:574092 [View Article] [PubMed]
     [Google Scholar]
  15. Laarman AJ, Mijnheer G, Mootz JM, van Rooijen WJM, Ruyken M et al. Staphylococcus aureus Staphopain A inhibits CXCR2-dependent neutrophil activation and chemotaxis. EMBO J 2012; 31:3607–3619 [View Article] [PubMed]
     [Google Scholar]
  16. Kielian T, Barry B, Hickey WF. CXC chemokine receptor-2 ligands are required for neutrophil-mediated host defense in experimental brain abscesses. J Immunol 2001; 166:4634–4643 [View Article] [PubMed]
     [Google Scholar]
  17. Ye D, Yang K, Zang S, Lin Z, Chau H-T et al. Lipocalin-2 mediates non-alcoholic steatohepatitis by promoting neutrophil-macrophage crosstalk via the induction of CXCR2. J Hepatol 2016; 65:988–997 [View Article] [PubMed]
     [Google Scholar]
  18. Di Mitri D, Mirenda M, Vasilevska J, Calcinotto A, Delaleu N et al. Re-education of tumor-associated macrophages by CXCR2 blockade drives senescence and tumor inhibition in advanced prostate cancer. Cell Rep 2019; 28:2156–2168 [View Article] [PubMed]
     [Google Scholar]
  19. Fey PD, Endres JL, Yajjala VK, Widhelm TJ, Boissy RJ et al. A genetic resource for rapid and comprehensive phenotype screening of nonessential Staphylococcus aureus genes. mBio 2013; 4:e00537-12 [View Article] [PubMed]
     [Google Scholar]
  20. Mosialou I, Shikhel S, Liu J-M, Maurizi A, Luo N et al. MC4R-dependent suppression of appetite by bone-derived lipocalin 2. Nature 2017; 543:385–390 [View Article] [PubMed]
     [Google Scholar]
  21. Nam Y, Kim J-H, Seo M, Kim J-H, Jin M et al. Lipocalin-2 protein deficiency ameliorates experimental autoimmune encephalomyelitis: the pathogenic role of lipocalin-2 in the central nervous system and peripheral lymphoid tissues. J Biol Chem 2014; 289:16773–16789 [View Article] [PubMed]
     [Google Scholar]
  22. Rigby KM, DeLeo FR. Neutrophils in innate host defense against Staphylococcus aureus infections. Semin Immunopathol 2012; 34:237–259 [View Article] [PubMed]
     [Google Scholar]
  23. Guerra FE, Borgogna TR, Patel DM, Sward EW, Voyich JM. Epic immune battles of history: Neutrophils vs. Staphylococcus aureus. Front Cell Infect Microbiol 2017; 7:286 [View Article] [PubMed]
     [Google Scholar]
  24. Scherr TD, Roux CM, Hanke ML, Angle A, Dunman PM et al. Global transcriptome analysis of Staphylococcus aureus biofilms in response to innate immune cells. Infect Immun 2013; 81:4363–4376 [View Article] [PubMed]
     [Google Scholar]
  25. Heim CE, Bosch ME, Yamada KJ, Aldrich AL, Chaudhari SS et al. Lactate production by Staphylococcus aureus biofilm inhibits HDAC11 to reprogramme the host immune response during persistent infection. Nat Microbiol 2020; 5:1271–1284 [View Article] [PubMed]
     [Google Scholar]
  26. Heim CE, Vidlak D, Odvody J, Hartman CW, Garvin KL et al. Human prosthetic joint infections are associated with myeloid-derived suppressor cells (MDSCs): implications for infection persistence. J Orthop Res 2018; 36:1605–1613 [View Article] [PubMed]
     [Google Scholar]
  27. O’Byrne PM, Metev H, Puu M, Richter K, Keen C et al. Efficacy and safety of a CXCR2 antagonist, AZD5069, in patients with uncontrolled persistent asthma: a randomised, double-blind, placebo-controlled trial. Lancet Respir Med 2016; 4:797–806 [View Article] [PubMed]
     [Google Scholar]
  28. De Soyza A, Pavord I, Elborn JS, Smith D, Wray H et al. A randomised, placebo-controlled study of the CXCR2 antagonist AZD5069 in bronchiectasis. Eur Respir J 2015; 46:1021–1032 [View Article] [PubMed]
     [Google Scholar]
  29. Wang Q, Li S, Tang X, Liang L, Wang F et al. Lipocalin 2 protects against Escherichia coli infection by modulating neutrophil and macrophage function. Front Immunol 2019; 10:2594 [View Article] [PubMed]
     [Google Scholar]
  30. Nairz M, Schroll A, Haschka D, Dichtl S, Sonnweber T et al. Lipocalin-2 ensures host defense against Salmonella Typhimurium by controlling macrophage iron homeostasis and immune response. Eur J Immunol 2015; 45:3073–3086 [View Article] [PubMed]
     [Google Scholar]
  31. Xiao X, Yeoh BS, Vijay-Kumar M. Lipocalin 2: an emerging player in iron homeostasis and inflammation. Annu Rev Nutr 2017; 37:103–130 [View Article] [PubMed]
     [Google Scholar]
  32. Flo TH, Smith KD, Sato S, Rodriguez DJ, Holmes MA et al. Lipocalin 2 mediates an innate immune response to bacterial infection by sequestrating iron. Nature 2004; 432:917–921 [View Article] [PubMed]
     [Google Scholar]
  33. Kirsten AM, Förster K, Radeczky E, Linnhoff A, Balint B et al. The safety and tolerability of oral AZD5069, a selective CXCR2 antagonist, in patients with moderate-to-severe COPD. Pulm Pharmacol Ther 2015; 31:36–41 [View Article] [PubMed]
     [Google Scholar]
  34. Warszawska JM, Gawish R, Sharif O, Sigel S, Doninger B et al. Lipocalin 2 deactivates macrophages and worsens pneumococcal pneumonia outcomes. J Clin Invest 2013; 123:3363–3372 [View Article] [PubMed]
     [Google Scholar]
  35. Gries CM, Bruger EL, Moormeier DE, Scherr TD, Waters CM et al. Cyclic di-AMP released from Staphylococcus aureus biofilm induces a macrophage type I interferon response. Infect Immun 2016; 84:3564–3574 [View Article] [PubMed]
     [Google Scholar]
  36. Acker G, Zollfrank J, Jelgersma C, Nieminen-Kelhä M, Kremenetskaia I et al. The CXCR2/CXCL2 signalling pathway - an alternative therapeutic approach in high-grade glioma. Eur J Cancer 2020; 126:106–115 [View Article] [PubMed]
     [Google Scholar]
  37. Hanke ML, Angle A, Kielian T. MyD88-dependent signaling influences fibrosis and alternative macrophage activation during Staphylococcus aureus biofilm infection. PLoS One 2012; 7:e42476 [View Article] [PubMed]
     [Google Scholar]
  38. Metzemaekers M, Gouwy M, Proost P. Neutrophil chemoattractant receptors in health and disease: double-edged swords. Cell Mol Immunol 2020; 17:433–450 [View Article] [PubMed]
     [Google Scholar]
  39. Guardado S, Ojeda-Juárez D, Kaul M, Nordgren TM. Comprehensive review of lipocalin 2-mediated effects in lung inflammation. Am J Physiol Lung Cell Mol Physiol 2021; 321:L726–L733 [View Article] [PubMed]
     [Google Scholar]
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CXCR2 perturbation promotes Staphylococcus aureus implant-associated infection
J. Med. Microbiol. 73, 001821 (2024); https://doi.org/10.1099/jmm.0.001821
/content/journal/jmm/10.1099/jmm.0.001821
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