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An Interaction of LPS and RSV Infection in Augmenting the AHR and Airway Inflammation in Mice

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Abstract

Respiratory syncytial virus (RSV) is the leading cause of acute lower respiratory tract infection (LRTI) in children under 5 years of age, especially infants with severe bronchiolitis. Our preliminary clinical experiments showed that bacterial colonization was commonly observed in children with virus-induced wheezing, particularly in those with recurrent wheezing, suggesting that bacterial colonization with an accompanying viral infection may contribute to disease severity. In most cases, RSV-infected infants were colonized with pathogenic bacteria (mainly Gram-negative bacteria). LPS is the main component of Gram-negative bacteria and acts as a ligand for Toll-like receptor 4 (TLR4). Relevant studies have reported that the TLR family is crucial in mediating the link between viral components and immunologic responses to infection. Of note, TLR4 activation has been associated with disease severity during RSV infection. In the present study, we identified that LPS aggravated RSV-induced AHR and airway inflammation in BALB/c mice using an RSV coinfection model. We found that the airway inflammatory cells and cytokines present in BALF and TRIF in lung tissue play a role in inducing AHR and airway inflammation upon RSV and bacteria coinfection, which might occur through the TRIF-MMP-9-neutrophil-MMP-9 signalling pathway. These results may aid in the development of novel treatments and improve vaccine design.

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References

  1. Collins, P.L., and J.A. Melero. 2011. Progress in understanding and controlling respiratory syncytial virus: still crazy after all these years. Virus Research 162 (1–2): 80–99. doi:10.1016/j.virusres.2011.09.020.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Escobar, Gabriel J., Anthony S. Masaquel, Sherian X. Li, Eileen M. Walsh, and Patricia Kipnis. 2013. Persistent recurring wheezing in the fifth year of life after laboratory-confirmed, medically attended respiratory syncytial virus infection in infancy. BMC Pediatrics 13 (1): 97.

    Article  PubMed  PubMed Central  Google Scholar 

  3. Wu, P., and T.V. Hartert. 2011. Evidence for a causal relationship between respiratory syncytial virus infection and asthma. Expert Review of Anti-Infective Therapy 9 (9): 731–745. doi:10.1586/eri.11.92.

    Article  PubMed  PubMed Central  Google Scholar 

  4. Bacharier, Leonard B., Rebecca Cohen, Toni Schweiger, Huiquing Yin-DeClue, Chandrika Christie, Jie Zheng, Kenneth B. Schechtman, Robert C. Strunk, and Mario Castro. 2012. Determinants of asthma after severe respiratory syncytial virus bronchiolitis. Journal of Allergy and Clinical Immunology 130 (1): 91–100. e103.

    Article  PubMed  PubMed Central  Google Scholar 

  5. Sigurs, Nele, Fatma Aljassim, Bengt Kjellman, Paul D. Robinson, Fridrik Sigurbergsson, Ragnar Bjarnason, and Per M. Gustafsson. 2010. Asthma and allergy patterns over 18 years after severe RSV bronchiolitis in the first year of life. Thorax 65 (12): 1045–1052.

    Article  PubMed  Google Scholar 

  6. Cooper, Ben S., Daniel M. Weinberger, Keith P. Klugman, Claudia A. Steiner, Lone Simonsen, and Cécile Viboud. 2015. Association between respiratory syncytial virus activity and pneumococcal disease in infants: a time series analysis of US hospitalization data. PLoS Medicine 12 (1): e1001776. doi:10.1371/journal.pmed.1001776.

    Article  Google Scholar 

  7. Thorburn, K., S. Harigopal, V. Reddy, N. Taylor, and H.K. van Saene. 2006. High incidence of pulmonary bacterial co-infection in children with severe respiratory syncytial virus (RSV) bronchiolitis. Thorax 61 (7): 611–615. doi:10.1136/thx.2005.048397.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Yu, Deng, Liu Wei, Zhengxiu Luo, Jian Luo, Lijia Wang, Xiqiang Yang, Zhao Xiaodong, Fu Zhou, and Liu Enmei. 2010. Impact of bacterial colonization on the severity, and accompanying airway inflammation, of virus-induced wheezing in children. Clinical Microbiology and Infection 16 (9): 1399–1404.

    Article  CAS  PubMed  Google Scholar 

  9. De Schutter, I., A. Dreesman, O. Soetens, M. De Waele, F. Crokaert, J. Verhaegen, D. Pierard, and A. Malfroot. 2012. In young children, persistent wheezing is associated with bronchial bacterial infection: a retrospective analysis. BMC Pediatrics 12: 83. doi:10.1186/1471-2431-12-83.

    Article  PubMed  PubMed Central  Google Scholar 

  10. Suarez-Arrabal, M.C., C. Mella, S.M. Lopez, N.V. Brown, M.W. Hall, S. Hammond, W. Shiels, et al. 2015. Nasopharyngeal bacterial burden and antibiotics: Influence on inflammatory markers and disease severity in infants with respiratory syncytial virus bronchiolitis. The Journal of Infection 71 (4): 458–469. doi:10.1016/j.jinf.2015.06.010.

    Article  PubMed  Google Scholar 

  11. Avadhanula, Vasanthi, Yan Wang, Allen Portner, and Elisabeth Adderson. 2007. Nontypeable Haemophilus influenzae and Streptococcus pneumoniae bind respiratory syncytial virus glycoprotein. Journal of Medical Microbiology 56 (9): 1133–1137.

    Article  CAS  PubMed  Google Scholar 

  12. Avadhanula, V., C.A. Rodriguez, J.P. Devincenzo, Y. Wang, R.J. Webby, G.C. Ulett, and E.E. Adderson. 2006. Respiratory viruses augment the adhesion of bacterial pathogens to respiratory epithelium in a viral species- and cell type-dependent manner. Journal of Virology 80 (4): 1629–1636. doi:10.1128/JVI.80.4.1629-1636.2006.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Gagro, Alenka, Mirna Tominac, Vilka Kršulović-Hrešić, Ana Baće, Mladen Matić, Vladimir Draženović, Gordana Mlinarić-Galinović, Ela Kosor, Katja Gotovac, and Ivan Bolanča. 2004. Increased Toll-like receptor 4 expression in infants with respiratory syncytial virus bronchiolitis. Clinical & Experimental Immunology 135 (2): 267–272.

    Article  CAS  Google Scholar 

  14. Jorquera, Patricia A., Katie E. Oakley, and Ralph A. Tripp. 2013. Advances in and the potential of vaccines for respiratory syncytial virus. Expert Review of Respiratory Medicine 7 (4): 411–427.

    Article  CAS  PubMed  Google Scholar 

  15. Xie, Xiao-Hong, Helen K.W. Law, Li-Jia Wang, Xin Li, Xi-Qiang Yang, and En-Mei Liu. 2009. Lipopolysaccharide induces IL-6 production in respiratory syncytial virus-infected airway epithelial cells through the toll-like receptor 4 signaling pathway. Pediatric Research 65 (2): 156–162.

    Article  CAS  PubMed  Google Scholar 

  16. Kong, M.Y., J.P. Clancy, N. Peng, Y. Li, T.J. Szul, X. Xu, R. Oster, et al. 2014. Pulmonary matrix metalloproteinase-9 activity in mechanically ventilated children with respiratory syncytial virus. The European Respiratory Journal 43 (4): 1086–1096. doi:10.1183/09031936.00105613.

    Article  CAS  PubMed  Google Scholar 

  17. Bradley, L.M., Douglass, M.F., Chatterjee, D., Akira, S.,and Baaten, B.J.. 2012. Matrix metalloprotease 9 mediates neutrophil migration into the airways in response to influenza virus-induced toll-like receptor signaling. PLoS pathogens 8 (4).

  18. Famakin, B.M., Y. Mou, K. Johnson, M. Spatz, and J. Hallenbeck. 2014. A new role for downstream Toll-like receptor signaling in mediating immediate early gene expression during focal cerebral ischemia. Journal of Cerebral Blood Flow and Metabolism 34 (2): 258–267. doi:10.1038/jcbfm.2013.182.

    Article  CAS  PubMed  Google Scholar 

  19. Sethi, S., J. Maloney, L. Grove, C. Wrona, and C.S. Berenson. 2006. Airway inflammation and bronchial bacterial colonization in chronic obstructive pulmonary disease. American Journal of Respiratory and Critical Care Medicine 173 (9): 991–998. doi:10.1164/rccm.200509-1525OC.

    Article  PubMed  PubMed Central  Google Scholar 

  20. Zang, N., X. Xie, Y. Deng, S. Wu, L. Wang, C. Peng, S. Li, K. Ni, Y. Luo, and E. Liu. 2011. Resveratrol-mediated gamma interferon reduction prevents airway inflammation and airway hyperresponsiveness in respiratory syncytial virus-infected immunocompromised mice. Journal of Virology 85 (24): 13061–13068. doi:10.1128/JVI.05869-11.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Long, X., S. Li, J. Xie, W. Li, N. Zang, L. Ren, Y. Deng, et al. 2015. MMP-12-mediated by SARM-TRIF signaling pathway contributes to IFN-gamma-independent airway inflammation and AHR post RSV infection in nude mice. Respiratory Research 16: 11. doi:10.1186/s12931-015-0176-8.

    Article  PubMed  PubMed Central  Google Scholar 

  22. Zang, Na, Simin Li, Wei Lia, Xiaohong Xie, Luo Ren, Xiaoru Long, Jun Xie, Yu Deng, Zhou Fu, Fadi Xu, and Liu Enmei. 2015. Resveratrol suppresses persistent airway inflammation and hyperresponsivess might partially via nerve growth factor in respiratory syncytial virus-infected mice. International Immunopharmacology 28(1): 8

  23. Hu, A., M. Colella, J.S. Tam, R. Rappaport, and S.M. Cheng. 2003. Simultaneous detection, subgrouping, and quantitation of respiratory syncytial virus a and B by real-time PCR. Journal of Clinical Microbiology 41 (1): 149–154. doi:10.1128/jcm.41.1.149-154.2003.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Peebles, R. Stokes, James R. Sheller, Robert D. Collins, A. Kasia Jarzecka, Daphne B. Mitchell, Robert A. Parker, and Barney S. Graham. 2001. Respiratory syncytial virus infection does not increase allergen-induced type 2 cytokine production, yet increases airway hyperresponsiveness in mice. Journal of Medical Virology 63 (2): 178–188.

    Article  CAS  PubMed  Google Scholar 

  25. de Steenhuijsen Piters, W.A., Heinonen, S., Hasrat, R., Bunsow, E., Smith, B., Suarez-Arrabal, M.C., Chaussabel, D., Cohen, D.M., Sanders, E.A., Ramilo, O., Bogaert, D.,and Mejias, A.. 2016. Nasopharyngeal microbiota, host transcriptome and disease severity in children with respiratory syncytial virus infection. Am J Respir Crit Care Med.

  26. Stoppelenburg, A.J., V. Salimi, M. Hennus, M. Plantinga, Veld R. in’t Huis, J. Walk, J. Meerding, F. Coenjaerts, L. Bont, and M. Boes. 2013. Local IL-17A potentiates early neutrophil recruitment to the respiratory tract during severe RSV infection. PloS One 8 (10): e78461. doi:10.1371/journal.pone.0078461.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Savov, J.D., S.H. Gavett, D.M. Brass, D.L. Costa, and D.A. Schwartz. 2002. Neutrophils play a critical role in development of LPS-induced airway disease. American Journal of Physiology. Lung Cellular and Molecular Physiology 283 (5): L952–L962. doi:10.1152/ajplung.00420.2001.

    Article  CAS  PubMed  Google Scholar 

  28. Puthothu, B., M. Krueger, J. Heinze, J. Forster, and A. Heinzmann. 2006. Impact of IL8 and IL8-receptor alpha polymorphisms on the genetics of bronchial asthma and severe RSV infections. Clin Mol Allergy 4: 2. doi:10.1186/1476-7961-4-2.

    Article  PubMed  PubMed Central  Google Scholar 

  29. Wang, Changtian, Demin Li, Yajun Qian, Jun Wang, and Hua Jing. 2012. Increased matrix metalloproteinase-9 activity and mRNA expression in lung injury following cardiopulmonary bypass. Laboratory Investigation 92 (6): 910–916. doi:10.1038/labinvest.2012.50.

    Article  CAS  PubMed  Google Scholar 

  30. Bradley, L.M., M.F. Douglass, D. Chatterjee, S. Akira, and B.J. Baaten. 2012. Matrix metalloprotease 9 mediates neutrophil migration into the airways in response to influenza virus-induced toll-like receptor signaling. PLoS Pathogens 8 (4): e1002641. doi:10.1371/journal.ppat.1002641.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. McNamara, P.S., P. Ritson, A. Selby, C.A. Hart, and R.L. Smyth. 2003. Bronchoalveolar lavage cellularity in infants with severe respiratory syncytial virus bronchiolitis. Archives of disease in childhood. 88 (10): 6.

    Article  Google Scholar 

  32. Sadik, C.D., N.D. Kim, and A.D. Luster. 2011. Neutrophils cascading their way to inflammation. Trends in Immunology 32 (10): 452–460. doi:10.1016/j.it.2011.06.008.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Xiao, Q., S. Zheng, L. Zhou, L. Ren, X. Xie, Y. Deng, D. Tian, Y. Zhao, Z. Fu, T. Li, A. Huang, and E. Liu. 2015. Impact of human rhinovirus types and viral load on the severity of illness in hospitalized children with lower respiratory tract infections. The Pediatric Infectious Disease Journal 34 (11): 6.

    Article  Google Scholar 

  34. Houben, M.L., F.E. Coenjaerts, J.W. Rossen, M.E. Belderbos, R.W. Hofland, J.L. Kimpen, and L. Bont. 2010. Disease severity and viral load are correlated in infants with primary respiratory syncytial virus infection in the community. Journal of Medical Virology 82 (7): 1266–1271.

    Article  CAS  PubMed  Google Scholar 

  35. Haynes, L.M., D.D. Moore, E.A. Kurt-Jones, R.W. Finberg, L.J. Anderson, and R.A. Tripp. 2001. Involvement of toll-like receptor 4 in innate immunity to respiratory syncytial virus. Journal of Virology 75 (22): 10730–10737. doi:10.1128/JVI.75.22.10730-10737.2001.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Caballero, M.T., M.E. Serra, and P.L. Acosta. 2015. TLR4 genotype and environmental LPS mediate RSV bronchiolitis through Th2 polarization. The Journal of Clinical Investigation 125 (2): 571–582. doi:10.1172/jci75183ds1.

    Article  PubMed  PubMed Central  Google Scholar 

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Acknowledgments

This work is supported by the fund of the National Natural Science Foundation of China (Nos. 81501742 and 81470208).

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Correspondence to Enmei Liu.

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Zhou, N., Li, W., Ren, L. et al. An Interaction of LPS and RSV Infection in Augmenting the AHR and Airway Inflammation in Mice. Inflammation 40, 1643–1653 (2017). https://doi.org/10.1007/s10753-017-0604-7

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