1887

Abstract

Chronic pulmonary infection is associated with colonization with multiple micro-organisms but host–microbe and microbe–microbe interactions are poorly understood.

This study aims to investigate the differences in host responses to mono- and co-infection with and in human airway epithelial cells.

We assessed the effect of co-infection with and on host signalling and inflammatory responses in the human airway epithelial cell line 16HBE, using ELISA and western blot analysis.

The results show that activates MAPK and NF-κB signalling pathways, subsequently eliciting robust interleukin (IL)-8 production. However, when airway epithelial cells were co-treated with live bacteria and supernatants (conditioned medium), the pro-inflammatory response was attenuated. This anti-inflammatory effect was widely exhibited in the isolates tested and was mediated via reduced MAPK and NF-κB signalling, but not via IL-1 receptor or tumour necrosis factor receptor modulation. The staphylococcal effectors were characterized as small, heat-stable, non-proteinaceous and not cell wall-related factors.

This study demonstrates for the first time the host response in a / co-infection model and provides insight into a staphylococcal immune evasion mechanism, as well as a therapeutic intervention for excessive inflammation.

Funding
This study was supported by the:
  • University of Bath
    • Principle Award Recipient: Yuan Ji
Loading

Article metrics loading...

/content/journal/jmm/10.1099/jmm.0.001100
2019-11-01
2024-03-28
Loading full text...

Full text loading...

/deliver/fulltext/jmm/68/12/1813.html?itemId=/content/journal/jmm/10.1099/jmm.0.001100&mimeType=html&fmt=ahah

References

  1. Troeger C, Forouzanfar M, Rao PC, Khalil I, Brown A et al. Estimates of the global, regional, and national morbidity, mortality, and aetiologies of lower respiratory tract infections in 195 countries: a systematic analysis for the global burden of disease study 2015. Lancet Infect Dis 2017; 17:1133–1161 [View Article]
    [Google Scholar]
  2. Pragman AA, Berger JP, Williams BJ. Understanding persistent bacterial lung infections: clinical implications informed by the biology of the microbiota and biofilms. Clin Pulm Med 2016; 23:57–66 [View Article]
    [Google Scholar]
  3. 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]
    [Google Scholar]
  4. Haaber J, Penadés JR, Ingmer H. Transfer of antibiotic resistance in Staphylococcus aureus . Trends Microbiol 2017; 25:893–905 [View Article]
    [Google Scholar]
  5. Thammavongsa V, Kim HK, Missiakas D, Schneewind O. Staphylococcal manipulation of host immune responses. Nat Rev Microbiol 2015; 13:529–543 [View Article]
    [Google Scholar]
  6. Dasenbrook EC, Checkley W, Merlo CA, Konstan MW, Lechtzin N et al. Association between respiratory tract methicillin-resistant Staphylococcus aureus and survival in cystic fibrosis. JAMA 2010; 303:2386–2392 [View Article]
    [Google Scholar]
  7. Moran GJ, Krishnadasan A, Gorwitz RJ, Fosheim GE, Albrecht V et al. Prevalence of methicillin-resistant Staphylococcus aureus as an etiology of community-acquired pneumonia. Clin Infect Dis 2012; 54:1126–1133 [View Article]
    [Google Scholar]
  8. Hauser N, Orsini J. Cepacia syndrome in a non-cystic fibrosis patient. Case Rep Infect Dis 2015; 2015:1–4 [View Article]
    [Google Scholar]
  9. Kenna DTD, Lilley D, Coward A, Martin K, Perry C et al. Prevalence of Burkholderia species, including members of Burkholderia cepacia complex, among UK cystic and non-cystic fibrosis patients. J Med Microbiol 2017; 66:490–501 [View Article]
    [Google Scholar]
  10. LiPuma JJ, Mortensen JE, Dasen SE, Edlind TD, Schidlow DV et al. Ribotype analysis of Pseudomonas cepacia from cystic fibrosis treatment centers. J Pediatr 1988; 113:859–862 [View Article]
    [Google Scholar]
  11. Palfreyman RW, Watson ML, Eden C, Smith AW. Induction of biologically active interleukin-8 from lung epithelial cells by Burkholderia (Pseudomonas) cepacia products. Infect Immun 1997; 65:617–622
    [Google Scholar]
  12. Oliveira MEF, Araújo DG, Oliveira SR. Resistance of non-fermenting gram-negative bacilli isolated from blood cultures from an emergency Hospital. J Bras Patol Med Lab 2017; 53:87–91
    [Google Scholar]
  13. Shommu NS, Vogel HJ, Storey DG. Potential of metabolomics to reveal Burkholderia cepacia complex pathogenesis and antibiotic resistance. Front Microbiol 2015; 6:668 [View Article]
    [Google Scholar]
  14. Cystic Fibrosis Foundation Cystic Fibrosis Foundation Patient Registry 2016 Annual Data Report Maryland: Bethesda; 2017
    [Google Scholar]
  15. Leitão JH, Sousa SA, Ferreira AS, Ramos CG, Silva IN et al. Pathogenicity, virulence factors, and strategies to fight against Burkholderia cepacia complex pathogens and related species. Appl Microbiol Biotechnol 2010; 87:31–40 [View Article]
    [Google Scholar]
  16. Urban TA, Goldberg JB, Forstner JF, Sajjan US. Cable pili and the 22-kilodalton adhesin are required for Burkholderia cenocepacia binding to and transmigration across the squamous epithelium. Infect Immun 2005; 73:5426–5437 [View Article]
    [Google Scholar]
  17. Urban TA, Griffith A, Torok AM, Smolkin ME, Burns JL et al. Contribution of Burkholderia cenocepacia flagella to infectivity and inflammation. Infect Immun 2004; 72:5126–5134 [View Article]
    [Google Scholar]
  18. De Soyza A, Silipo A, Lanzetta R, Govan JR, Molinaro A. Chemical and biological features of Burkholderia cepacia complex lipopolysaccharides. Innate Immun 2008; 14:127–144 [View Article]
    [Google Scholar]
  19. Tisoncik JR, Korth MJ, Simmons CP, Farrar J, Martin TR et al. Into the eye of the cytokine storm. Microbiol Mol Biol Rev 2012; 76:16–32 [View Article]
    [Google Scholar]
  20. Orazi G, O’Toole GA. Pseudomonas aeruginosa Alters Staphylococcus aureus Sensitivity to Vancomycin in a Biofilm Model of Cystic Fibrosis Infection. MBio 2017; 8:e00873-174 [View Article]
    [Google Scholar]
  21. Perez AC, Pang B, King LB, Tan L, Murrah KA et al. Residence of Streptococcus pneumoniae and Moraxella catarrhalis within polymicrobial biofilm promotes antibiotic resistance and bacterial persistence in vivo . Pathog Dis 2014; 70:280–288 [View Article]
    [Google Scholar]
  22. Ramsey MM, Whiteley M. Polymicrobial interactions stimulate resistance to host innate immunity through metabolite perception. Proc Natl Acad Sci USA 2009; 106:1578–1583 [View Article]
    [Google Scholar]
  23. Bragonzi A, Farulla I, Paroni M, Twomey KB, Pirone L et al. Modelling co-infection of the cystic fibrosis lung by Pseudomonas aeruginosa and Burkholderia cenocepacia reveals influences on biofilm formation and host response. PLoS One 2012; 7:e52330 [View Article]
    [Google Scholar]
  24. Fugère A, Lalonde Séguin D, Mitchell G, Déziel E, Dekimpe V et al. Interspecific small molecule interactions between clinical isolates of Pseudomonas aeruginosa and Staphylococcus aureus from adult cystic fibrosis patients. PLoS One 2014; 9:e86705 [View Article]
    [Google Scholar]
  25. Korgaonkar A, Trivedi U, Rumbaugh KP, Whiteley M. Community surveillance enhances Pseudomonas aeruginosa virulence during polymicrobial infection. Proc Natl Acad Sci USA 2013; 110:1059–1064 [View Article]
    [Google Scholar]
  26. Emerson J, Rosenfeld M, McNamara S, Ramsey B, Gibson RL. Pseudomonas aeruginosa and other predictors of mortality and morbidity in young children with cystic fibrosis. Pediatr Pulmonol 2002; 34:91–100 [View Article]
    [Google Scholar]
  27. Liou TG, Adler FR, Fitzsimmons SC, Cahill BC, Hibbs JR et al. Predictive 5-year survivorship model of cystic fibrosis. Am J Epidemiol 2001; 153:345–352 [View Article]
    [Google Scholar]
  28. Mayer-Hamblett N, Aitken ML, Accurso FJ, Kronmal RA, Konstan MW et al. Association between pulmonary function and sputum biomarkers in cystic fibrosis. Am J Respir Crit Care Med 2007; 175:822–828 [View Article]
    [Google Scholar]
  29. Nixon GM, Armstrong DS, Carzino R, Carlin JB, Olinsky A et al. Clinical outcome after early Pseudomonas aeruginosa infection in cystic fibrosis. J Pediatr 2001; 138:699–704 [View Article]
    [Google Scholar]
  30. 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]
    [Google Scholar]
  31. Wachsmann P, Lamprecht A. Polymeric nanoparticles for the selective therapy of inflammatory bowel disease. Methods Enzymol 2012; 508:377–397 [View Article]
    [Google Scholar]
  32. Perret M, Badiou C, Lina G, Burbaud S, Benito Y et al. Cross-talk between Staphylococcus aureus leukocidins-intoxicated macrophages and lung epithelial cells triggers chemokine secretion in an inflammasome-dependent manner. Cell Microbiol 2012; 14:1019–1036 [View Article]
    [Google Scholar]
  33. Dennehy R, Romano M, Ruggiero A, Mohamed YF, Dignam SL et al. The Burkholderia cenocepacia peptidoglycan-associated lipoprotein is involved in epithelial cell attachment and elicitation of inflammation. Cell Microbiol 2017; 19:e12691 [View Article]
    [Google Scholar]
  34. Peres AG, Stegen C, Li J, Xu AQ, Levast B et al. Uncoupling of pro- and anti-inflammatory properties of Staphylococcus aureus . Infect Immun 2015; 83:1587–1597 [View Article]
    [Google Scholar]
  35. Pandey S, Kawai T, Akira S. Microbial sensing by Toll-like receptors and intracellular nucleic acid sensors. Cold Spring Harb Perspect Biol 2014; 7:a016246 [View Article]
    [Google Scholar]
  36. Hoffmann E, Dittrich-Breiholz O, Holtmann H, Kracht M. Multiple control of interleukin-8 gene expression. J Leukoc Biol 2002; 72:847–855
    [Google Scholar]
  37. Gómez MI, Lee A, Reddy B, Muir A, Soong G et al. Staphylococcus aureus protein A induces airway epithelial inflammatory responses by activating TNFR1. Nat Med 2004; 10:842–848 [View Article]
    [Google Scholar]
  38. Labrousse D, Perret M, Hayez D, Da Silva S, Badiou C et al. Kineret®/IL-1ra blocks the IL-1/IL-8 inflammatory cascade during recombinant Panton Valentine Leukocidin-triggered pneumonia but not during S. aureus infection. PLoS One 2014; 9:e97546 [View Article]
    [Google Scholar]
  39. 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; 15:918 [View Article]
    [Google Scholar]
  40. Baldan R, Cigana C, Testa F, Bianconi I, De Simone M et al. Adaptation of Pseudomonas aeruginosa in Cystic Fibrosis airways influences virulence of Staphylococcus aureus in vitro and murine models of co-infection. PLoS One 2014; 9:e89614 [View Article]
    [Google Scholar]
  41. Chekabab SM, Silverman RJ, Lafayette SL, Luo Y, Rousseau S et al. Staphylococcus aureus inhibits IL-8 responses induced by Pseudomonas aeruginosa in airway epithelial cells. PLoS One 2015; 10:e0137753–19 [View Article]
    [Google Scholar]
  42. DeLeon S, Clinton A, Fowler H, Everett J, Horswill AR et al. Synergistic interactions of Pseudomonas aeruginosa and Staphylococcus aureus in an in vitro wound model. Infect Immun 2014; 82:4718–4728 [View Article]
    [Google Scholar]
  43. McCarthy AJ, Lindsay JA. Staphylococcus aureus innate immune evasion is lineage-specific: a bioinfomatics study. Infection, Genetics and Evolution 2013; 19:7–14 [View Article]
    [Google Scholar]
  44. Krachler AM, Woolery AR, Orth K. Manipulation of kinase signaling by bacterial pathogens. J Cell Biol 2011; 195:1083–1092 [View Article]
    [Google Scholar]
  45. Gillette DD, Shah PA, Cremer T, Gavrilin MA, Besecker BY et al. Analysis of human bronchial epithelial cell proinflammatory response to Burkholderia cenocepacia infection: inability to secrete IL-1β. J Biol Chem 2013; 288:3691–3695 [View Article]
    [Google Scholar]
  46. Sajjan US, Hershenson MB, Forstner JF, LiPuma JJ. Burkholderia cenocepacia ET12 strain activates TNFR1 signalling in cystic fibrosis airway epithelial cells. Cell Microbiol 2008; 10:188–201 [View Article]
    [Google Scholar]
  47. D'Elia RV, Saint RJ, Newstead SL, Clark GC, Atkins HS. Mitogen-activated protein kinases (MAPKs) are modulated during in vitro and in vivo infection with the intracellular bacterium Burkholderia pseudomallei . Eur J Clin Microbiol Infect Dis 2017; 36:2147–2154 [View Article]
    [Google Scholar]
  48. Li Y, Jiang Z, Xue D, Deng G, Li M et al. Mycoplasma ovipneumoniae induces sheep airway epithelial cell apoptosis through an ERK signalling-mediated mitochondria pathway. BMC Microbiol 2016; 16:222 [View Article]
    [Google Scholar]
  49. Tajima A, Seki K, Shinji H, Masuda S. Inhibition of interleukin-8 production in human endothelial cells by Staphylococcus aureus supernatant. Clin Exp Immunol 2006; 147:148–154 [View Article]
    [Google Scholar]
  50. Graille M, Stura EA, Corper AL, Sutton BJ, Taussig MJ 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 USA 2000; 97:5399–5404 [View Article]
    [Google Scholar]
  51. Soong G, Martin FJ, Chun J, Cohen TS, Ahn DS et al. Staphylococcus aureus protein A mediates invasion across airway epithelial cells through activation of RhoA GTPase signaling and proteolytic activity. J Biol Chem 2011; 286:35891–35898 [View Article]
    [Google Scholar]
  52. Carey RM, Chen B, Adappa ND, Palmer JN, Kennedy DW et al. Human upper airway epithelium produces nitric oxide in response to Staphylococcus epidermidis . Int Forum Allergy Rhinol 2016; 6:1238–1244 [View Article]
    [Google Scholar]
  53. Carey RM, Workman AD, Chen B, Adappa ND, Palmer JN et al. Staphylococcus aureus triggers nitric oxide production in human upper airway epithelium. Int Forum Allergy Rhinol 2015; 5:808–813 [View Article]
    [Google Scholar]
  54. Askarian F, van Sorge NM, Sangvik M, Beasley FC, Henriksen JR et al. A Staphylococcus aureus TIR domain protein virulence factor blocks TLR2-mediated NF-κB signaling. J Innate Immun 2014; 6:485–498 [View Article]
    [Google Scholar]
  55. Koymans KJ, Goldmann O, Karlsson CAQ, Sital W, Thänert R et al. The TLR2 antagonist staphylococcal superantigen-like protein 3 acts as a virulence factor to promote bacterial pathogenicity in vivo . J Innate Immun 2017; 9:561–573 [View Article]
    [Google Scholar]
  56. Chu M, Zhou M, Jiang C, Chen X, Guo L et al. Staphylococcus aureus phenol-soluble modulins α1–α3 act as novel Toll-like receptor (TLR) 4 antagonists to inhibit HMGB1/TLR4/NF-κB signaling pathway. Front Immunol 2018; 9:596–13 [View Article]
    [Google Scholar]
  57. Holden MTG, Feil EJ, Lindsay JA, Peacock SJ, Day NPJ et al. Complete genomes of two clinical Staphylococcus aureus strains: evidence for the rapid evolution of virulence and drug resistance. Proc Natl Acad Sci USA 2004; 101:9786–9791 [View Article]
    [Google Scholar]
  58. Baba T, Bae T, Schneewind O, Takeuchi F, Hiramatsu K. Genome sequence of Staphylococcus aureus strain Newman and comparative analysis of staphylococcal genomes: polymorphism and evolution of two major pathogenicity islands. J Bacteriol 2008; 190:300–310 [View Article]
    [Google Scholar]
  59. Collins J, Rudkin J, Recker M, Pozzi C, O'Gara JP et al. Offsetting virulence and antibiotic resistance costs by MRSA. Isme J 2010; 4:577–584 [View Article]
    [Google Scholar]
  60. O'Neill AJ. Staphylococcus aureus SH1000 and 8325-4: comparative genome sequences of key laboratory strains in staphylococcal research. Lett Appl Microbiol 2010; 51:358–361 [View Article]
    [Google Scholar]
  61. Nair D, Memmi G, Hernandez D, Bard J, Beaume M et al. Whole-genome sequencing of Staphylococcus aureus strain RN4220, a key laboratory strain used in virulence research, identifies mutations that affect not only virulence factors but also the fitness of the strain. J Bacteriol 2011; 193:2332–2335 [View Article]
    [Google Scholar]
  62. Voyich JM, Otto M, Mathema B, Braughton KR, Whitney AR et al. Is Panton-Valentine leukocidin the major virulence determinant in community-associated methicillin-resistant Staphylococcus aureus disease?. J Infect Dis 2006; 194:1761–1770 [View Article]
    [Google Scholar]
  63. Holden MTG, Seth-Smith HMB, Crossman LC, Sebaihia M, Bentley SD et al. The genome of Burkholderia cenocepacia J2315, an epidemic pathogen of cystic fibrosis patients. J Bacteriol 2009; 191:261–277 [View Article]
    [Google Scholar]
http://instance.metastore.ingenta.com/content/journal/jmm/10.1099/jmm.0.001100
Loading
/content/journal/jmm/10.1099/jmm.0.001100
Loading

Data & Media loading...

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