1887

Microbiology Society logo

Volume 167, Issue 1

Editor's Choice An cystic fibrosis model recapitulates key clinical aspects of chronic infection Open Access

Abstract

is the most prevalent organism isolated from the airways of people with cystic fibrosis (CF), predominantly early in life. Yet its role in the pathology of lung disease is poorly understood. In mice, and many experiments using cell lines, the bacterium invades cells or interstitium, and forms abscesses. This is at odds with the limited available clinical data: interstitial bacteria are rare in CF biopsies and abscesses are highly unusual. Bacteria instead appear to localize in mucus plugs in the lumens of bronchioles. We show that, in an established model of CF infection comprising porcine bronchiolar tissue and synthetic mucus, demonstrates clinically significant characteristics including colonization of the airway lumen, with preferential localization as multicellular aggregates in mucus, initiation of a small colony variant phenotype and increased antibiotic tolerance of tissue-associated aggregates. Tissue invasion and abscesses were not observed. Our results may inform ongoing debates relating to clinical responses to in people with CF.

  • Received:
  • Accepted:
  • Published Online:
Keyword(s): 3Rs , antimicrobial resistance , biofilm , chronic infection , Cystic fibrosis and small colony variant
Funding
This study was supported by the:
  • Medical Research Council (Award MR/R001898/1)
    • Principle Award Recipient: Freya Harrison
© 2021 The Authors
Loading

Article metrics loading...

/content/journal/micro/10.1099/mic.0.000987
2020-11-13
2024-04-23
Loading full text...

Full text loading...

/deliver/fulltext/micro/167/1/micro000987.html?itemId=/content/journal/micro/10.1099/mic.0.000987&mimeType=html&fmt=ahah

References

  1. Ahlgren HG, Benedetti A, Landry JS, Bernier J, Matouk E et al. Clinical outcomes associated with Staphylococcus aureus and Pseudomonas aeruginosa airway infections in adult cystic fibrosis patients. BMC Pulm Med 2015; 15:15–67 [View Article][PubMed]
     [Google Scholar]
  2. Szaff M, Høiby N. Antibiotic treatment of Staphylococcus aureus infection in cystic fibrosis. Acta Paediatr Scand 1982; 71:821–826 [View Article][PubMed]
     [Google Scholar]
  3. Cystic Fibrosis Foundation Patient Registry 2018 Annual Data Report Cystic fibrosis Foundation; 2019
  4. Hurley MN. Staphylococcus Aureus in Cystic Fibrosis: Problem Bug or an Innocent Bystander? Breathe (Sheff) 14 England: 2018 pp 87–90
     [Google Scholar]
  5. Stone A, Quittell L, Zhou J, Alba L, Bhat M et al. Staphylococcus aureus nasal colonization among pediatric cystic fibrosis patients and their household contacts. Pediatr Infect Dis J 2009; 28:895–899 [View Article][PubMed]
     [Google Scholar]
  6. Fritz SA, Krauss MJ, Epplin EK, Burnham CA, Garbutt J et al. The natural history of contemporary Staphylococcus aureus nasal colonization in community children. Pediatr Infect Dis J 2011; 30:349–351 [View Article][PubMed]
     [Google Scholar]
  7. Rosenfeld M, Emerson J, Accurso F, Armstrong D, Castile R et al. Diagnostic accuracy of oropharyngeal cultures in infants and young children with cystic fibrosis. Pediatr Pulmonol 1999; 28:321–328 [View Article][PubMed]
     [Google Scholar]
  8. Armstrong DS, Grimwood K, Carlin JB, Carzino R, Olinsky A et al. Bronchoalveolar lavage or oropharyngeal cultures to identify lower respiratory pathogens in infants with cystic fibrosis. Pediatr Pulmonol 1996; 21:267–275 [View Article][PubMed]
     [Google Scholar]
  9. Limoli DH, Hoffman LR. Help, hinder, hide and harm: what can we learn from the interactions between Pseudomonas aeruginosa and Staphylococcus aureus during respiratory infections?. Thorax 2019; 74:684–692 [View Article][PubMed]
     [Google Scholar]
  10. Goerke C, Wolz C. Regulatory and genomic plasticity of Staphylococcus aureus during persistent colonization and infection. Int J Med Microbiol 2004; 294:195–202 [View Article][PubMed]
     [Google Scholar]
  11. Wolter DJ, Emerson JC, McNamara S, Buccat AM, Qin X et al. Staphylococcus aureus small-colony variants are independently associated with worse lung disease in children with cystic fibrosis. Clin Infect Dis 2013; 57:384–391 [View Article][PubMed]
     [Google Scholar]
  12. Kahl BC, Duebbers A, Lubritz G, Haeberle J, Koch HG et al. Population dynamics of persistent Staphylococcus aureus isolated from the airways of cystic fibrosis patients during a 6-year prospective study. J Clin Microbiol 2003; 41:4424–4427 [View Article][PubMed]
     [Google Scholar]
  13. Besier S, Smaczny C, von Mallinckrodt C, Krahl A, Ackermann H et al. Prevalence and clinical significance of Staphylococcus aureus small-colony variants in cystic fibrosis lung disease. J Clin Microbiol 2007; 45:168–172 [View Article][PubMed]
     [Google Scholar]
  14. Gangell C, Gard S, Douglas T, Park J, de Klerk N et al. Inflammatory responses to individual microorganisms in the lungs of children with cystic fibrosis. Clin Infect Dis 2011; 53:425–432 [View Article][PubMed]
     [Google Scholar]
  15. Sagel SD, Gibson RL, Emerson J, McNamara S, Burns JL et al. Impact of Pseudomonas and Staphylococcus infection on inflammation and clinical status in young children with cystic fibrosis. J Pediatr 2009; 154:183–188 [View Article][PubMed]
     [Google Scholar]
  16. Davis SD, Fordham LA, Brody AS, Noah TL, Retsch-Bogart GZ et al. Computed tomography reflects lower airway inflammation and tracks changes in early cystic fibrosis. Am J Respir Crit Care Med 2007; 175:943–950 [View Article][PubMed]
     [Google Scholar]
  17. Granchelli AM, Adler FR, Keogh RH, Kartsonaki C, Cox DR et al. Microbial interactions in the cystic fibrosis airway. J Clin Microbiol 2018; 56: [View Article][PubMed]
     [Google Scholar]
  18. Wong JK, Ranganathan SC, Hart E. Australian Respiratory Early Surveillance Team for Cystic Fibrosis (ARESTCF) Staphylococcus aureus in early cystic fibrosis lung disease. Pediatr Pulmonol 2013; 48:1151–1159 [View Article][PubMed]
     [Google Scholar]
  19. Ratjen F, Comes G, Paul K, Posselt HG, Wagner TO et al. Effect of continuous antistaphylococcal therapy on the rate of P. aeruginosa acquisition in patients with cystic fibrosis. Pediatr Pulmonol 2001; 31:13–16 [View Article][PubMed]
     [Google Scholar]
  20. Stutman HR, Lieberman JM, Nussbaum E, Marks MI. Antibiotic prophylaxis in infants and young children with cystic fibrosis: a randomized controlled trial. J Pediatr 2002; 140:299–305 [View Article][PubMed]
     [Google Scholar]
  21. Smyth AR, Rosenfeld M. Prophylactic anti-staphylococcal antibiotics for cystic fibrosis. Cochrane Database Syst Rev 2017; 4:Cd001912 [View Article][PubMed]
     [Google Scholar]
  22. Imundo L, Barasch J, Prince A, Al-Awqati Q. Cystic fibrosis epithelial cells have a receptor for pathogenic bacteria on their apical surface. Proc Natl Acad Sci U S A 1995; 92:3019–3023 [View Article][PubMed]
     [Google Scholar]
  23. Schwab UE, Wold AE, Carson JL, Leigh MW, Cheng PW et al. Increased adherence of Staphylococcus aureus from cystic fibrosis lungs to airway epithelial cells. Am Rev Respir Dis 1993; 148:365–369 [View Article][PubMed]
     [Google Scholar]
  24. McKenney D, Pouliot KL, Wang Y, Murthy V, Ulrich M et al. Broadly protective vaccine for Staphylococcus aureus based on an in vivo-expressed antigen. Science 1999; 284:1523–1527 [View Article][PubMed]
     [Google Scholar]
  25. Ulrich M, Herbert S, Berger J, Bellon G, Louis D et al. Localization of Staphylococcus aureus in infected airways of patients with cystic fibrosis and in a cell culture model of S. aureus adherence. Am J Respir Cell Mol Biol 1998; 19:83–91 [View Article][PubMed]
     [Google Scholar]
  26. Shuter J, Hatcher VB, Lowy FD. Staphylococcus aureus binding to human nasal mucin. Infect Immun 1996; 64:310–318 [View Article][PubMed]
     [Google Scholar]
  27. Sanford BA, Thomas VL, Ramsay MA. Binding of staphylococci to mucus in vivo and in vitro. Infect Immun 1989; 57:3735–3742 [View Article][PubMed]
     [Google Scholar]
  28. Bragonzi A. Murine models of acute and chronic lung infection with cystic fibrosis pathogens. Int J Med Microbiol 2010; 300:584–593 [View Article][PubMed]
     [Google Scholar]
  29. Lavelle GM, White MM, Browne N, McElvaney NG, Reeves EP. Animal models of cystic fibrosis pathology: phenotypic parallels and divergences. Biomed Res Int 2016; 2016:5258727 [View Article][PubMed]
     [Google Scholar]
  30. Cressman VL, Hicks EM, Funkhouser WK, Backlund DC, Koller BH. The relationship of chronic mucin secretion to airway disease in normal and CFTR-deficient mice. Am J Respir Cell Mol Biol 1998; 19:853–866 [View Article][PubMed]
     [Google Scholar]
  31. Cigana C, Bianconi I, Baldan R, De Simone M, Riva C et al. Staphylococcus aureus impacts Pseudomonas aeruginosa chronic respiratory disease in murine models. J Infect Dis 2018; 217:933–942 [View Article][PubMed]
     [Google Scholar]
  32. Kuhajda I, Zarogoulidis K, Tsirgogianni K, Tsavlis D, Kioumis I et al. Lung abscess-etiology, diagnostic and treatment options. Ann Transl Med 2015; 3:183 [View Article][PubMed]
     [Google Scholar]
  33. Patradoon-Ho P, Fitzgerald DA. Lung abscess in children. Paediatr Respir Rev 2007; 8:77–84 [View Article][PubMed]
     [Google Scholar]
  34. Canny GJ, Marcotte JE, Levison H. Lung abscess in cystic fibrosis. Thorax 1986; 41:221–222 [View Article][PubMed]
     [Google Scholar]
  35. Hurley MN, McKeever TM, Prayle AP, Fogarty AW, Smyth AR. Rate of improvement of CF life expectancy exceeds that of general population-observational death registration study. J Cyst Fibros 2014; 13:410–415 [View Article][PubMed]
     [Google Scholar]
  36. Andersen DH. Therapy and prognosis of fibrocystic disease of the pancreas. Pediatrics 1949; 3:406–417[PubMed]
     [Google Scholar]
  37. Palmer KL, Aye LM, Whiteley M. Nutritional cues control Pseudomonas aeruginosa multicellular behavior in cystic fibrosis sputum. J Bacteriol 2007; 189:8079–8087 [View Article][PubMed]
     [Google Scholar]
  38. Harrison F, Diggle SP. An ex vivo lung model to study bronchioles infected with Pseudomonas aeruginosa biofilms. Microbiology 2016; 162:1755–1760 [View Article][PubMed]
     [Google Scholar]
  39. Harrison F, Muruli A, Higgins S, Diggle SP. Development of an ex vivo porcine lung model for studying growth, virulence, and signaling of Pseudomonas aeruginosa. Infect Immun 2014; 82:3312–3323 [View Article][PubMed]
     [Google Scholar]
  40. Harrington NE, Sweeney E, Harrison F. Building a better biofilm - formation of in vivo -like biofilm structures by Pseudomonas aeruginosa in a porcine model of cystic fibrosis lung infection. bioRxiv 8585972019:
     [Google Scholar]
  41. Meurens F, Summerfield A, Nauwynck H, Saif L, Gerdts V. The pig: a model for human infectious diseases. Trends Microbiol 2012; 20:50–57 [View Article][PubMed]
     [Google Scholar]
  42. Williams PP, Gallagher JE. Preparation and long-term cultivation of porcine tracheal and lung organ cultures by alternate exposure to gaseous and liquid medium phases. In Vitro 1978; 14:686–696 [View Article][PubMed]
     [Google Scholar]
  43. Martineau F, Picard FJ, Ke D, Paradis S, Roy PH et al. Development of a PCR assay for identification of staphylococci at genus and species levels. J Clin Microbiol 2001; 39:2541–2547 [View Article][PubMed]
     [Google Scholar]
  44. Andrews JM. Determination of minimum inhibitory concentrations. J Antimicrob Chemother 2001; 48:5–16 [View Article][PubMed]
     [Google Scholar]
  45. Craig WA. Pharmacokinetic/Pharmacodynamic parameters: rationale for antibacterial dosing of mice and men. Clin Infect Dis 1998; 26:1–2 [View Article][PubMed]
     [Google Scholar]
  46. Bergan T. Penicillins. Antibiot Chemother 1971; 1978:1–122
     [Google Scholar]
  47. Vanhommerig E, Moons P, Pirici D, Lammens C, Hernalsteens JP et al. Comparison of biofilm formation between major clonal lineages of methicillin resistant Staphylococcus aureus . PLoS One 2014; 9:e104561 [View Article][PubMed]
     [Google Scholar]
  48. Goerke C, Wolz C. Adaptation of Staphylococcus aureus to the cystic fibrosis lung. Int J Med Microbiol 2010; 300:520–525 [View Article][PubMed]
     [Google Scholar]
  49. Smyth A. Update on treatment of pulmonary exacerbations in cystic fibrosis. Curr Opin Pulm Med 2006; 12:440–444 [View Article][PubMed]
     [Google Scholar]
  50. DePas WH, Starwalt-Lee R, Van Sambeek L, Ravindra Kumar S, Gradinaru V et al. Exposing the three-dimensional biogeography and metabolic states of pathogens in cystic fibrosis sputum via hydrogel embedding, clearing, and rRNA labeling. mBio 2016; 7:e00796-16 [View Article][PubMed]
     [Google Scholar]
  51. Kahl BC, Becker K, Löffler B. Clinical significance and pathogenesis of staphylococcal small colony variants in persistent infections. Clin Microbiol Rev 2016; 29:401–427 [View Article][PubMed]
     [Google Scholar]
  52. Baltimore RS, Christie CD, Smith GJ. Immunohistopathologic localization of Pseudomonas aeruginosa in lungs from patients with cystic fibrosis. Implications for the pathogenesis of progressive lung deterioration. Am Rev Respir Dis 1989; 140:1650–1661 [View Article][PubMed]
     [Google Scholar]
  53. Bjarnsholt T, Jensen Peter Østrup, Fiandaca MJ, Pedersen J, Hansen CR et al. Pseudomonas aeruginosa biofilms in the respiratory tract of cystic fibrosis patients. Pediatr Pulmonol 2009; 44:547–558 [View Article][PubMed]
     [Google Scholar]
  54. Henderson AG, Ehre C, Button B, Abdullah LH, Cai LH et al. Cystic fibrosis airway secretions exhibit mucin hyperconcentration and increased osmotic pressure. J Clin Invest 2014; 124:3047–3060 [View Article][PubMed]
     [Google Scholar]
  55. Potts SB, Roggli VL, Spock A. Immunohistologic quantification of Pseudomonas aeruginosa in the tracheobronchial tree from patients with cystic fibrosis. Pediatr Pathol Lab Med 1995; 15:707–721 [View Article][PubMed]
     [Google Scholar]
  56. de Jong PA, Nakano Y, Lequin MH, Mayo JR, Woods R et al. Progressive damage on high resolution computed tomography despite stable lung function in cystic fibrosis. Eur Respir J 2004; 23:93–97 [View Article][PubMed]
     [Google Scholar]
  57. Dovey M, Wisseman CL, Roggli VL, Roomans GM, Shelburne JD et al. Ultrastructural morphology of the lung in cystic fibrosis. J Submicrosc Cytol Pathol 1989; 21:521–534[PubMed]
     [Google Scholar]
  58. Sawai T, Tomono K, Yanagihara K, Yamamoto Y, Kaku M et al. Role of coagulase in a murine model of hematogenous pulmonary infection induced by intravenous injection of Staphylococcus aureus enmeshed in agar beads. Infect Immun 1997; 65:466–471 [View Article][PubMed]
     [Google Scholar]
  59. Hirschhausen N, Block D, Bianconi I, Bragonzi A, Birtel J et al. Extended Staphylococcus aureus persistence in cystic fibrosis is associated with bacterial adaptation. Int J Med Microbiol 2013; 303:685–692 [View Article][PubMed]
     [Google Scholar]
  60. Madhani K, McGrath E, Guglani L. A 10-year retrospective review of pediatric lung abscesses from a single center. Ann Thorac Med 2016; 11:191–196 [View Article][PubMed]
     [Google Scholar]
  61. Elizur A, Orscheln RC, Ferkol TW, Atkinson JJ, Dunne WM et al. Panton-Valentine leukocidin-positive methicillin-resistant Staphylococcus aureus lung infection in patients with cystic fibrosis. Chest 2007; 131:1718–1725 [View Article][PubMed]
     [Google Scholar]
  62. Lester LA, Egge A, Hubbard VS, Di Sant' Agnese PA. Aspiration and lung abscess in cystic fibrosis. Am Rev Respir Dis 1983; 127:786–787 [View Article][PubMed]
     [Google Scholar]
  63. Goss CH, Muhlebach MS. Review: Staphylococcus aureus and MRSA in cystic fibrosis. J Cyst Fibros 2011; 10:298–306 [View Article][PubMed]
     [Google Scholar]
  64. Proctor RA, von Eiff C, Kahl BC, Becker K, McNamara P et al. Small colony variants: a pathogenic form of bacteria that facilitates persistent and recurrent infections. Nat Rev Microbiol 2006; 4:295–305 [View Article][PubMed]
     [Google Scholar]
  65. Davies D. Understanding biofilm resistance to antibacterial agents. Nat Rev Drug Discov 2003; 2:114–122 [View Article][PubMed]
     [Google Scholar]
  66. Kriegeskorte A, Grubmüller S, Huber C, Kahl BC, von Eiff C et al. Staphylococcus aureus small colony variants show common metabolic features in central metabolism irrespective of the underlying auxotrophism. Front Cell Infect Microbiol 2014; 4:141 [View Article][PubMed]
     [Google Scholar]
  67. Sifri CD, Baresch-Bernal A, Calderwood SB, von Eiff C. Virulence of Staphylococcus aureus small colony variants in the Caenorhabditis elegans infection model. Infect Immun 2006; 74:1091–1096 [View Article][PubMed]
     [Google Scholar]
  68. Ou JJJ, Drilling AJ, Cooksley C, Bassiouni A, Kidd SP et al. Reduced innate immune response to a Staphylococcus aureus small colony variant compared to its wild-type parent strain. Front Cell Infect Microbiol 2016; 6:187 [View Article][PubMed]
     [Google Scholar]
  69. Tuchscherr L, Medina E, Hussain M, Völker W, Heitmann V et al. Staphylococcus aureus phenotype switching: an effective bacterial strategy to escape host immune response and establish a chronic infection. EMBO Mol Med 2011; 3:129–141 [View Article][PubMed]
     [Google Scholar]
  70. Lipuma JJ. The changing microbial epidemiology in cystic fibrosis. Clin Microbiol Rev 2010; 23:299–323 [View Article][PubMed]
     [Google Scholar]
http://instance.metastore.ingenta.com/content/journal/micro/10.1099/mic.0.000987
Loading
An ex vivo cystic fibrosis model recapitulates key clinical aspects of chronic Staphylococcus aureus infection
Microbiology 167, 000987 (2021); https://doi.org/10.1099/mic.0.000987
/content/journal/micro/10.1099/mic.0.000987
/content/journal/micro/10.1099/mic.0.000987
Loading

Data & Media loading...

Supplements

Supplementary material 1

PDF

Most cited Most Cited RSS feed

This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error