{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,12]],"date-time":"2026-03-12T07:22:59Z","timestamp":1773300179551,"version":"3.50.1"},"reference-count":30,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2016,3,4]],"date-time":"2016-03-04T00:00:00Z","timestamp":1457049600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2016,3,4]],"date-time":"2016-03-04T00:00:00Z","timestamp":1457049600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"abstract":"<jats:title>Abstract<\/jats:title><jats:p>There is emerging epidemiological data to suggest that upper respiratory tract bacterial colonisation in infancy may increase the risk of developing respiratory dysfunction later in life and respiratory viruses are known to precipitate persistent colonisation. This study utilized a neonatal mouse model of <jats:italic>Streptococcus pneumonia<\/jats:italic> (SP) and influenza A virus (IAV) co-infection, where bronchoalveolar leukocyte infiltration had resolved by adulthood. Only co-infection resulted in persistent nasopharyngeal colonisation over 40 days and a significant increase in airway resistance in response to <jats:italic>in vivo<\/jats:italic> methacholine challenge. A significant increase in hysteresivity was also observed in IAV and co-infected mice, consistent with ventilatory heterogeneity and structural changes in the adult lung. Airway hyper-responsiveness was not associated with a detectable increase in goblet cell transdifferentiation, peribronchial smooth muscle bulk or collagen deposition in regions surrounding the airways. Increased reactivity was not observed in precision cut lung slices challenged with methacholine <jats:italic>in vitro<\/jats:italic>. Histologically, the airway epithelium appeared normal and expression of epithelial integrity markers (ZO-1, occludin-1 and E-cadherin) were not altered. In summary, neonatal co-infection led to persistent nasopharyngeal colonisation and increased airway responsiveness that was not associated with detectable smooth muscle or mucosal epithelial abnormalities, however increased hysteresivity may reflect ventilation heterogeneity.<\/jats:p>","DOI":"10.1038\/srep22751","type":"journal-article","created":{"date-parts":[[2016,3,4]],"date-time":"2016-03-04T11:31:42Z","timestamp":1457091102000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Neonatal pneumococcal colonisation caused by Influenza A infection alters lung function in adult mice"],"prefix":"10.1038","volume":"6","author":[{"given":"Meaghan","family":"FitzPatrick","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Simon G.","family":"Royce","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shenna","family":"Langenbach","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jonathan","family":"McQualter","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Patrick C.","family":"Reading","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Odilia","family":"Wijburg","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gary P.","family":"Anderson","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alastair","family":"Stewart","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jane","family":"Bourke","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Steven","family":"Bozinovski","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2016,3,4]]},"reference":[{"key":"BFsrep22751_CR1","doi-asserted-by":"publisher","first-page":"1333","DOI":"10.1001\/jama.292.11.1333","volume":"292","author":"WW Thompson","year":"2004","unstructured":"Thompson, W. W. et al. Influenza-associated hospitalizations in the United States. JAMA 292, 1333\u201340 (2004).","journal-title":"JAMA"},{"key":"BFsrep22751_CR2","doi-asserted-by":"publisher","first-page":"1917","DOI":"10.1016\/S0140-6736(11)61051-9","volume":"378","author":"H Nair","year":"2011","unstructured":"Nair, H. et al. Global burden of respiratory infections due to seasonal influenza in young children: a systematic review and meta-analysis. Lancet 378, 1917\u201330 (2011).","journal-title":"Lancet"},{"key":"BFsrep22751_CR3","doi-asserted-by":"publisher","first-page":"1427","DOI":"10.1093\/cid\/cis211","volume":"54","author":"H Zhou","year":"2012","unstructured":"Zhou, H. et al. Hospitalizations associated with influenza and respiratory syncytial virus in the United States, 1993\u20132008. Clin Infect Dis. 54, 1427\u201336 (2012).","journal-title":"Clin Infect Dis."},{"key":"BFsrep22751_CR4","doi-asserted-by":"publisher","first-page":"77","DOI":"10.1126\/science.1119392","volume":"310","author":"TM Tumpey","year":"2005","unstructured":"Tumpey, T. M. et al. Characterization of the reconstructed 1918 Spanish influenza pandemic virus. Science 310, 77\u201380 (2005).","journal-title":"Science"},{"key":"BFsrep22751_CR5","doi-asserted-by":"publisher","first-page":"718","DOI":"10.1097\/00006454-200107000-00018","volume":"20","author":"RA Adegbola","year":"2001","unstructured":"Adegbola, R. A., Obaro, S. K., Biney, E. & Greenwood, B. M. Evaluation of Binax now Streptococcus pneumoniae urinary antigen test in children in a community with a high carriage rate of pneumococcus. Pediatr Infect Dis J 20, 718\u20139 (2001).","journal-title":"Pediatr Infect Dis J"},{"key":"BFsrep22751_CR6","doi-asserted-by":"publisher","first-page":"784","DOI":"10.1086\/313772","volume":"30","author":"KL O\u2019Brien","year":"2000","unstructured":"O\u2019Brien, K. L. et al. Severe pneumococcal pneumonia in previously healthy children: the role of preceding influenza infection. Clin Infect Dis. 30, 784\u20139 (2000).","journal-title":"Clin Infect Dis."},{"key":"BFsrep22751_CR7","doi-asserted-by":"publisher","first-page":"1789","DOI":"10.1096\/fj.09-146779","volume":"24","author":"DA Diavatopoulos","year":"2010","unstructured":"Diavatopoulos, D. A. et al. Influenza A virus facilitates Streptococcus pneumoniae transmission and disease. FASEB J 24, 1789\u201398 (2010).","journal-title":"FASEB J"},{"key":"BFsrep22751_CR8","doi-asserted-by":"publisher","first-page":"1208","DOI":"10.1016\/j.jaci.2015.05.003","volume":"136","author":"CJ Carlsson","year":"2015","unstructured":"Carlsson, C. J. et al. Duration of wheezy episodes in early childhood is independent of the microbial trigger. J Allergy Clin Immunol 136, 1208\u20131214 e5 (2015).","journal-title":"J Allergy Clin Immunol"},{"key":"BFsrep22751_CR9","doi-asserted-by":"publisher","first-page":"611","DOI":"10.1136\/thx.2005.048397","volume":"61","author":"K Thorburn","year":"2006","unstructured":"Thorburn, K., Harigopal, S., Reddy, V., Taylor, N. & van Saene, H. K. High incidence of pulmonary bacterial co-infection in children with severe respiratory syncytial virus (RSV) bronchiolitis. Thorax 61, 611\u20135 (2006).","journal-title":"Thorax"},{"key":"BFsrep22751_CR10","doi-asserted-by":"publisher","first-page":"1246","DOI":"10.1164\/rccm.201302-0215OC","volume":"188","author":"NH Vissing","year":"2013","unstructured":"Vissing, N. H., Chawes, B. L. & Bisgaard, H. Increased risk of pneumonia and bronchiolitis after bacterial colonization of the airways as neonates. Am J Respir Crit Care Med 188, 1246\u201352 (2013).","journal-title":"Am J Respir Crit Care Med"},{"key":"BFsrep22751_CR11","doi-asserted-by":"publisher","first-page":"1487","DOI":"10.1056\/NEJMoa052632","volume":"357","author":"H Bisgaard","year":"2007","unstructured":"Bisgaard, H. et al. Childhood asthma after bacterial colonization of the airway in neonates. N Engl J Med 357, 1487\u201395 (2007).","journal-title":"N Engl J Med"},{"key":"BFsrep22751_CR12","doi-asserted-by":"publisher","first-page":"457","DOI":"10.1111\/j.1398-9995.2007.01341.x","volume":"62","author":"NG Papadopoulos","year":"2007","unstructured":"Papadopoulos, N. G. et al. Mechanisms of virus-induced asthma exacerbations: state-of-the-art. A GA2LEN and InterAirways document. Allergy 62, 457\u201370 (2007).","journal-title":"Allergy"},{"key":"BFsrep22751_CR13","doi-asserted-by":"publisher","first-page":"190","DOI":"10.1016\/j.resp.2008.06.011","volume":"162","author":"EM Bozanich","year":"2008","unstructured":"Bozanich, E. M. et al. Acute Influenza A infection induces bronchial hyper-responsiveness in mice. Respir Physiol Neurobiol 162, 190\u20136 (2008).","journal-title":"Respir Physiol Neurobiol"},{"key":"BFsrep22751_CR14","doi-asserted-by":"publisher","first-page":"334","DOI":"10.1111\/j.1750-2659.2011.00236.x","volume":"5","author":"AN Larcombe","year":"2011","unstructured":"Larcombe, A. N. et al. Sexual dimorphism in lung function responses to acute influenza A infection. Influenza Other Respir Viruses 5, 334\u201342 (2011).","journal-title":"Influenza Other Respir Viruses"},{"key":"BFsrep22751_CR15","doi-asserted-by":"publisher","first-page":"179","DOI":"10.1164\/rccm.201211-2139OC","volume":"188","author":"D Anthony","year":"2013","unstructured":"Anthony, D. et al. Serum amyloid A promotes lung neutrophilia by increasing IL-17A levels in the mucosa and gammadelta T cells. Am J Respir Crit Care Med 188, 179\u201386 (2013).","journal-title":"Am J Respir Crit Care Med"},{"key":"BFsrep22751_CR16","doi-asserted-by":"publisher","first-page":"2408","DOI":"10.1152\/jappl.1989.67.6.2408","volume":"67","author":"JJ Fredberg","year":"1989","unstructured":"Fredberg, J. J. & Stamenovic, D. On the imperfect elasticity of lung tissue. Journal of Applied Physiology 67, 2408\u20132419 (1989).","journal-title":"Journal of Applied Physiology"},{"key":"BFsrep22751_CR17","doi-asserted-by":"publisher","first-page":"68","DOI":"10.1016\/j.pupt.2013.11.005","volume":"28","author":"M FitzPatrick","year":"2014","unstructured":"FitzPatrick, M., Donovan, C. & Bourke, J. E. Prostaglandin E2 elicits greater bronchodilation than salbutamol in mouse intrapulmonary airways in lung slices. Pulm Pharmacol Ther 28, 68\u201376 (2014).","journal-title":"Pulm Pharmacol Ther"},{"key":"BFsrep22751_CR18","doi-asserted-by":"crossref","first-page":"180","DOI":"10.1165\/rcmb.2013-0008OC","volume":"50","author":"SG Royce","year":"2014","unstructured":"Royce, S. G. et al. Mechanistic insights into the contribution of epithelial damage to airway remodeling. Novel therapeutic targets for asthma. Am J Respir Cell Mol Biol 50, 180\u201392 (2014).","journal-title":"Am J Respir Cell Mol Biol"},{"key":"BFsrep22751_CR19","doi-asserted-by":"publisher","first-page":"110","DOI":"10.1186\/1465-9921-14-110","volume":"14","author":"KE Gabehart","year":"2013","unstructured":"Gabehart, K. E. et al. Airway hyperresponsiveness is associated with airway remodeling but not inflammation in aging Cav1\u2212\/\u2212 mice. Respir Res 14, 110 (2013).","journal-title":"Respir Res"},{"key":"BFsrep22751_CR20","doi-asserted-by":"publisher","first-page":"229","DOI":"10.1165\/rcmb.2010-0272OC","volume":"45","author":"S Bozinovski","year":"2011","unstructured":"Bozinovski, S. et al. Carbonylation caused by cigarette smoke extract is associated with defective macrophage immunity. Am J Respir Cell Mol Biol. 45, 229\u201336 (2011).","journal-title":"Am J Respir Cell Mol Biol."},{"key":"BFsrep22751_CR21","doi-asserted-by":"crossref","unstructured":"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 (2011).","DOI":"10.1128\/mBio.00172-11"},{"key":"BFsrep22751_CR22","doi-asserted-by":"publisher","first-page":"144","DOI":"10.1016\/S1473-3099(04)00938-7","volume":"4","author":"D Bogaert","year":"2004","unstructured":"Bogaert, D., De Groot, R. & Hermans, P. W. Streptococcus pneumoniae colonisation: the key to pneumococcal disease. Lancet Infect Dis 4, 144\u201354 (2004).","journal-title":"Lancet Infect Dis"},{"key":"BFsrep22751_CR23","doi-asserted-by":"publisher","first-page":"627","DOI":"10.1038\/mi.2014.95","volume":"8","author":"R Wilson","year":"2015","unstructured":"Wilson, R. et al. Protection against Streptococcus pneumoniae lung infection after nasopharyngeal colonization requires both humoral and cellular immune responses. Mucosal Immunol 8, 627\u201339 (2015).","journal-title":"Mucosal Immunol"},{"key":"BFsrep22751_CR24","doi-asserted-by":"publisher","first-page":"558","DOI":"10.1038\/nm1765","volume":"14","author":"K Sun","year":"2008","unstructured":"Sun, K. & Metzger, D. W. Inhibition of pulmonary antibacterial defense by interferon-gamma during recovery from influenza infection. Nat Med 14, 558\u201364 (2008).","journal-title":"Nat Med"},{"key":"BFsrep22751_CR25","doi-asserted-by":"publisher","first-page":"7441","DOI":"10.4049\/jimmunol.0902497","volume":"183","author":"MD Tate","year":"2009","unstructured":"Tate, M. D. et al. Neutrophils ameliorate lung injury and the development of severe disease during influenza infection. J Immunol 183, 7441\u201350 (2009).","journal-title":"J Immunol"},{"key":"BFsrep22751_CR26","doi-asserted-by":"publisher","first-page":"4611","DOI":"10.4049\/jimmunol.1101299","volume":"188","author":"AN Thorburn","year":"2012","unstructured":"Thorburn, A. N., Foster, P. S., Gibson, P. G. & Hansbro, P. M. Components of Streptococcus pneumoniae suppress allergic airways disease and NKT cells by inducing regulatory T cells. J Immunol 188, 4611\u201320 (2012).","journal-title":"J Immunol"},{"key":"BFsrep22751_CR27","doi-asserted-by":"publisher","first-page":"1202","DOI":"10.1016\/j.jaci.2010.01.024","volume":"125","author":"PD Sly","year":"2010","unstructured":"Sly, P. D., Kusel, M. & Holt, P. G. Do early-life viral infections cause asthma? J Allergy Clin Immunol 125, 1202\u20135 (2010).","journal-title":"J Allergy Clin Immunol"},{"key":"BFsrep22751_CR28","doi-asserted-by":"publisher","first-page":"726","DOI":"10.1038\/nm.2768","volume":"18","author":"PG Holt","year":"2012","unstructured":"Holt, P. G. & Sly, P. D. Viral infections and atopy in asthma pathogenesis: new rationales for asthma prevention and treatment. Nat Med 18, 726\u201335 (2012).","journal-title":"Nat Med"},{"key":"BFsrep22751_CR29","doi-asserted-by":"publisher","first-page":"704","DOI":"10.1016\/j.chom.2015.03.008","volume":"17","author":"SM Teo","year":"2015","unstructured":"Teo, S. M. et al. The infant nasopharyngeal microbiome impacts severity of lower respiratory infection and risk of asthma development. Cell Host Microbe 17, 704\u201315 (2015).","journal-title":"Cell Host Microbe"},{"key":"BFsrep22751_CR30","doi-asserted-by":"publisher","first-page":"1111","DOI":"10.1152\/japplphysiol.01244.2010","volume":"110","author":"B Suki","year":"2011","unstructured":"Suki, B. & Bates, J. H. Lung tissue mechanics as an emergent phenomenon. J Appl Physiol (1985) 110, 1111\u20138 (2011).","journal-title":"J Appl Physiol (1985)"}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/srep22751","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/srep22751.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/srep22751.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,1,4]],"date-time":"2023-01-04T12:54:59Z","timestamp":1672836899000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/srep22751"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2016,3,4]]},"references-count":30,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2016,9,2]]}},"alternative-id":["BFsrep22751"],"URL":"https:\/\/doi.org\/10.1038\/srep22751","relation":{},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2016,3,4]]},"assertion":[{"value":"10 November 2015","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"19 February 2016","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"4 March 2016","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing financial interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"22751"}}