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Direct interactions with influenza promote bacterial adherence during respiratory infections

Nature Microbiology volume 4, pages 1328–1336 (2019)Cite this article

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Abstract

Epidemiological observations and animal models have long shown synergy between influenza virus infections and bacterial infections. Influenza virus infection leads to an increase in both the susceptibility to secondary bacterial infections and the severity of the bacterial infections, primarily pneumonias caused by Streptococcus pneumoniae or Staphylococcus aureus. We show that, in addition to the widely described immune modulation and tissue-remodelling mechanisms of bacterial–viral synergy, the virus interacts directly with the bacterial surface. Similar to the recent observation of direct interactions between enteric bacteria and enteric viruses, we observed a direct interaction between influenza virus on the surface of Gram-positive, S. pneumoniae and S. aureus, and Gram-negative, Moraxella catarrhalis and non-typeable Haemophilus influenzae, bacterial colonizers and pathogens in the respiratory tract. Pre-incubation of influenza virus with bacteria, followed by the removal of unbound virus, increased bacterial adherence to respiratory epithelial cells in culture. This result was recapitulated in vivo, with higher bacterial burdens in murine tissues when infected with pneumococci pre-incubated with influenza virus versus control bacteria without virus. These observations support an additional mechanism of bacteria–influenza virus synergy at the earliest steps of pathogenesis.

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Fig. 1: Influenza co-sediments with S. pneumoniae and is bound to the bacterial surface.
Fig. 2: Quatification of binding by flow cytometry.
Fig. 3: Surface-bound influenza enhances the adherence of S. pneumoniae.
Fig. 4: Influenza binds to the surface of multiple Gram-positive and Gram-negative bacterial respiratory pathogens.
Fig. 5: Surface-bound influenza enhances the adherence of multiple bacterial species to mammalian respiratory cells.
Fig. 6: Surface-bound influenza enhances the initial colonization of nasal passages and translocation into the middle ear, and lethal disease.

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Data availability

The data that support these findings are available from J. Rosch on request.

References

  1. Kuss, S. K. et al. Intestinal microbiota promote enteric virus replication and systemic pathogenesis. Science 334, 249–252 (2011).

    Article  CAS  Google Scholar 

  2. Erickson, A. K. et al. Bacteria facilitate enteric virus co-infection of mammalian cells and promote genetic recombination. Cell Host Microbe 23, 77–88 (2018).

    Article  CAS  Google Scholar 

  3. Robinson, C. M., Jesudhasan, P. R. & Pfeiffer, J. K. Bacterial lipopolysaccharide binding enhances virion stability and promotes environmental fitness of an enteric virus. Cell Host Microbe 15, 36–46 (2014).

    Article  CAS  Google Scholar 

  4. Berger, A. K., Yi, H., Kearns, D. B. & Mainou, B. A. Bacteria and bacterial envelope components enhance mammalian reovirus thermostability. PLoS Pathog. 13, e1006768 (2017).

    Article  Google Scholar 

  5. Pfeiffer, J. K. & Virgin, H. W. Viral immunity. Transkingdom control of viral infection and immunity in the mammalian intestine. Science 351, aad5872 (2016).

    Article  Google Scholar 

  6. Karst, S. M. The influence of commensal bacteria on infection with enteric viruses. Nat. Rev. Microbiol. 14, 197–204 (2016).

    Article  CAS  Google Scholar 

  7. Berger, A. K. & Mainou, B. A. Interactions between enteric bacteria and eukaryotic viruses impact the outcome of infection. Viruses 10, 19 (2018).

  8. Falsey, A. R. et al. Bacterial complications of respiratory tract viral illness: a comprehensive evaluation. J. Infect. Dis. 208, 432–441 (2013).

    Article  CAS  Google Scholar 

  9. McCullers, J. A. Do specific virus-bacteria pairings drive clinical outcomes of pneumonia? Clin. Microbiol. Infect. 19, 113–118 (2013).

    Article  CAS  Google Scholar 

  10. McCullers, J. A. & Rehg, J. E. Lethal synergism between influenza virus and Streptococcus pneumoniae: characterization of a mouse model and the role of platelet-activating factor receptor. J. Infect. Dis. 186, 341–350 (2002).

    Article  CAS  Google Scholar 

  11. McCullers, J. A. The co-pathogenesis of influenza viruses with bacteria in the lung. Nat. Rev. Microbiol. 12, 252–262 (2014).

    Article  CAS  Google Scholar 

  12. Ghoneim, H. E., Thomas, P. G. & McCullers, J. A. Depletion of alveolar macrophages during influenza infection facilitates bacterial superinfections. J. Immunol. 191, 1250–1259 (2013).

    Article  CAS  Google Scholar 

  13. Mina, M. J., Klugman, K. P., Rosch, J. W. & McCullers, J. A. Live attenuated influenza virus increases pneumococcal translocation and persistence within the middle ear. J. Infect. Dis. 212, 195–201 (2015).

    Article  CAS  Google Scholar 

  14. Smith, C. M. et al. Respiratory syncytial virus increases the virulence of Streptococcus pneumoniae by binding to penicillin binding protein 1a. A new paradigm in respiratory infection. Am. J. Respir. Crit. Care Med. 190, 196–207 (2014).

    Article  CAS  Google Scholar 

  15. Hament, J. M. et al. Direct binding of respiratory syncytial virus to pneumococci: a phenomenon that enhances both pneumococcal adherence to human epithelial cells and pneumococcal invasiveness in a murine model. Pediatr. Res. 58, 1198–1203 (2005).

    Article  CAS  Google Scholar 

  16. Avadhanula, V., Wang, Y., Portner, A. & Adderson, E. Nontypeable Haemophilus influenzae and Streptococcus pneumoniae bind respiratory syncytial virus glycoprotein. J. Med. Microbiol. 56, 1133–1137 (2007).

    Article  CAS  Google Scholar 

  17. Van Ewijk, B. E. et al. RSV mediates Pseudomonas aeruginosa binding to cystic fibrosis and normal epithelial cells. Pediatr. Res. 61, 398–403 (2007).

    Article  Google Scholar 

  18. Wu, N. H., Meng, F., Seitz, M., Valentin-Weigand, P. & Herrler, G. Sialic acid-dependent interactions between influenza viruses and Streptococcus suis affect the infection of porcine tracheal cells. J. Gen. Virol. 96, 2557–2568 (2015).

    Article  CAS  Google Scholar 

  19. Wang, Y. et al. Capsular sialic acid of Streptococcus suis serotype 2 binds to swine influenza virus and enhances bacterial interactions with virus-infected tracheal epithelial cells. Infect. Immun. 81, 4498–4508 (2013).

    Article  CAS  Google Scholar 

  20. Harding A. T., Heaton B. E., Dumm R. E. & Heaton N. S. Rationally designed influenza virus vaccines that are antigenically stable during growth in eggs. mBio 8, e00669-17 (2017).

  21. Rudd J. M., Ashar H. K., Chow V. T. & Teluguakula N. Lethal Synergism between Influenza and Streptococcus pneumoniae. J. Infect. Pulm. Dis. https://doi.org/10.16966/2470-3176.114 (2016).

  22. Edouard, S. et al. The nasopharyngeal microbiota in patients with viral respiratory tract infections is enriched in bacterial pathogens. Eur. J. Clin. Microbiol. Infect. Dis. 37, 1725–1733 (2018).

    Article  CAS  Google Scholar 

  23. Navne, J. E. et al. Nasopharyngeal bacterial carriage in young children in Greenland: a population at high risk of respiratory infections. Epidemiol. Infect. 144, 3226–3236 (2016).

    Article  CAS  Google Scholar 

  24. Huber, V. C., Thomas, P. G. & McCullers, J. A. A multi-valent vaccine approach that elicits broad immunity within an influenza subtype. Vaccine 27, 1192–1200 (2009).

    Article  CAS  Google Scholar 

  25. Rosch, J. W. et al. A live-attenuated pneumococcal vaccine elicits CD4+ T-cell dependent class switching and provides serotype independent protection against acute otitis media. EMBO Mol. Med. 6, 141–154 (2014).

    Article  CAS  Google Scholar 

  26. Kash J. C. et al. Lethal synergism of 2009 pandemic H1N1 influenza virus and Streptococcus pneumoniae coinfection is associated with loss of murine lung repair responses. mBio 2, e00172-11 (2011).

  27. Speshock, J. L., Doyon-Reale, N., Rabah, R., Neely, M. N. & Roberts, P. C. Filamentous influenza A virus infection predisposes mice to fatal septicemia following superinfection with Streptococcus pneumoniae serotype 3. Infect. Immun. 75, 3102–3111 (2007).

    Article  CAS  Google Scholar 

  28. Wolter, N. et al. High nasopharyngeal pneumococcal density, increased by viral coinfection, is associated with invasive pneumococcal pneumonia. J. Infect. Dis. 210, 1649–1657 (2014).

    Article  CAS  Google Scholar 

  29. El Ahmer, O. R., Raza, M. W., Ogilvie, M. M., Weir, D. M. & Blackwell, C. C. Binding of bacteria to HEp-2 cells infected with influenza A virus. FEMS Immunol. Med. Microbiol. 23, 331–341 (1999).

    Article  CAS  Google Scholar 

  30. Bandoro C. & Runstadler J. A. Bacterial lipopolysaccharide destabilizes influenza viruses. mSphere 2, e00267-17 (2017).

  31. King, S. J., Hippe, K. R. & Weiser, J. N. Deglycosylation of human glycoconjugates by the sequential activities of exoglycosidases expressed by Streptococcus pneumoniae. Mol. Microbiol. 59, 961–974 (2006).

    Article  CAS  Google Scholar 

  32. Heikkinen, T. & Chonmaitree, T. Importance of respiratory viruses in acute otitis media. Clin. Microbiol. Rev. 16, 230–241 (2003).

    Article  Google Scholar 

  33. Chonmaitree, T. et al. Viral upper respiratory tract infection and otitis media complication in young children. Clin. Infect. Dis. 46, 815–823 (2008).

    Article  Google Scholar 

  34. Wadowsky, R. M., Mietzner, S. M., Skoner, D. P., Doyle, W. J. & Fireman, P. Effect of experimental influenza A virus infection on isolation of Streptococcus pneumoniae and other aerobic bacteria from the oropharynges of allergic and nonallergic adult subjects. Infect. Immun. 63, 1153–1157 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Short, K. R. et al. Influenza virus induces bacterial and nonbacterial otitis media. J. Infect. Dis. 204, 1857–1865 (2011).

    Article  CAS  Google Scholar 

  36. Kim, J. K. & Cho, J. H. Change of external auditory canal pH in acute otitis externa. Ann. Otol. Rhinol. Laryngol. 118, 769–772 (2009).

    Article  Google Scholar 

  37. Weiser, J. N., Ferreira, D. M. & Paton, J. C. Streptococcus pneumoniae: transmission, colonization and invasion. Nat. Rev. Microbiol. 16, 355–367 (2018).

    Article  CAS  Google Scholar 

  38. Zafar, M. A., Wang, Y., Hamaguchi, S. & Weiser, J. N. Host-to-host transmission of Streptococcus pneumoniae is driven by its inflammatory toxin, pneumolysin. Cell Host Microbe 21, 73–83 (2017).

    Article  CAS  Google Scholar 

  39. Zafar, M. A., Kono, M., Wang, Y., Zangari, T. & Weiser, J. N. Infant mouse model for the study of shedding and transmission during Streptococcus pneumoniae monoinfection. Infect. Immun. 84, 2714–2722 (2016).

    Article  CAS  Google Scholar 

  40. Grijalva, C. G. et al. The role of influenza and parainfluenza infections in nasopharyngeal pneumococcal acquisition among young children. Clin. Infect. Dis. 58, 1369–1376 (2014).

    Article  Google Scholar 

  41. Harrison, A. et al. Genomic sequence of an otitis media isolate of nontypeable Haemophilus influenzae: comparative study with H. influenzae serotype d, strain KW20. J. Bacteriol. 187, 4627–4636 (2005).

    Article  CAS  Google Scholar 

  42. Helminen, M. E. et al. A large, antigenically conserved protein on the surface of Moraxella catarrhalis is a target for protective antibodies. J. Infect. Dis. 170, 867–872 (1994).

    Article  CAS  Google Scholar 

  43. Cline, T. D. et al. Increased pathogenicity of a reassortant 2009 pandemic H1N1 influenza virus containing an H5N1 hemagglutinin. J. Virol. 85, 12262–12270 (2011).

    Article  CAS  Google Scholar 

  44. Reed, L. J. & Meunch, H. A simple method of estimating fifty percent endpoints. Am. J. Hyg. 27, 493–497 (1938).

    Google Scholar 

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Acknowledgements

J.W.R. is supported by the National Institutes of Allergic and Infectious Diseases (NIAID) (grant nos. 1U01AI124302 and 1RO1AI110618). S.S.-C. is supported by the NIAID (grant no. HHSN272201400006C). J.W.R. and S.S.-C. are funded by the ALSAC. Images were acquired in the Cell and Tissue Imaging Center, which is supported by St. Jude and NCI P30 CA021765.

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Authors and Affiliations

  1. Department of Infectious Diseases, St. Jude Children’s Research Hospital, Memphis, TN, USA

    Hannah M. Rowe, Victoria A. Meliopoulos, Amy Iverson, Perrine Bomme, Stacey Schultz-Cherry & Jason W. Rosch

  2. UtechS Ultrastructural Bioimaging, Institut Pasteur, Paris, France

    Perrine Bomme

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Contributions

H.M.R., V.A.M., A.I. and P.B. performed the experiments. H.M.R., S.S.-C. and J.W.R. conceived and designed the experiments, and prepared the manuscript.

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Correspondence to Jason W. Rosch.

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Supplementary information

Supplementary Information

Supplementary Figures 1–3 and Supplementary Video legends.

Reporting Summary

Supplementary Video 1

3D rendering and rotation of SIM image of mRuby2–PR8 (red) on surface of S. pneumoniae stained with AF488-WGA (green). Representative from at least 10 bacterial–viral complexes.

Supplementary Video 2

3D rendering and rotation, and Z-stack slices of SIM image of mRuby2–PR8 (red) on surface of S. aureus stained with AF488-WGA (green). Representative from at least 10 bacterial-viral complexes.

Supplementary Video 3

3D rendering and rotation of SIM image of mRuby2–PR8 (red) on surface of M. catarrhalis stained with AF488-WGA (green). Representative from at least 10 bacterial–viral complexes.

Supplementary Video 4

3D rendering and rotation of SIM image of mRuby2–PR8 (red) on surface of H. influenzae stained with stained with MitoTracker DeepRed (false coloured to green). Representative from at least 10 bacterial–viral complexes.

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Rowe, H.M., Meliopoulos, V.A., Iverson, A. et al. Direct interactions with influenza promote bacterial adherence during respiratory infections. Nat Microbiol 4, 1328–1336 (2019). https://doi.org/10.1038/s41564-019-0447-0

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