{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,9]],"date-time":"2026-03-09T22:53:39Z","timestamp":1773096819315,"version":"3.50.1"},"reference-count":49,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2021,4,22]],"date-time":"2021-04-22T00:00:00Z","timestamp":1619049600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100006492","name":"Division of Intramural Research, National Institute of Allergy and Infectious Diseases","doi-asserted-by":"publisher","award":["Z01-AI-000943"],"award-info":[{"award-number":["Z01-AI-000943"]}],"id":[{"id":"10.13039\/100006492","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100006492","name":"Division of Intramural Research, National Institute of Allergy and Infectious Diseases","doi-asserted-by":"publisher","award":["Z01-AI-000647"],"award-info":[{"award-number":["Z01-AI-000647"]}],"id":[{"id":"10.13039\/100006492","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Viruses"],"abstract":"<jats:p>Respiratory virus infections can have long-term effects on lung function that persist even after the acute responses have resolved. Numerous studies have linked severe early childhood infection with respiratory syncytial virus (RSV) to the development of wheezing and asthma, although the underlying mechanisms connecting these observations remain unclear. Here, we examine airway hyperresponsiveness (AHR) that develops in wild-type mice after recovery from symptomatic but sublethal infection with the natural rodent pathogen, pneumonia virus of mice (PVM). We found that BALB\/c mice respond to a limited inoculum of PVM with significant but reversible weight loss accompanied by virus replication, acute inflammation, and neutrophil recruitment to the airways. At day 21 post-inoculation, virus was no longer detected in the airways and the acute inflammatory response had largely resolved. However, and in contrast to most earlier studies using the PVM infection model, all mice survived the initial infection and all went on to develop serum anti-PVM IgG antibodies. Furthermore, using both invasive plethysmography and precision-cut lung slices, we found that these mice exhibited significant airway hyperresponsiveness at day 21 post-inoculation that persisted through day 45. Taken together, our findings extend an important and versatile respiratory virus infection model that can now be used to explore the role of virions and virion clearance as well as virus-induced inflammatory mediators and their signaling pathways in the development and persistence of post-viral AHR and lung dysfunction.<\/jats:p>","DOI":"10.3390\/v13050728","type":"journal-article","created":{"date-parts":[[2021,4,22]],"date-time":"2021-04-22T21:25:56Z","timestamp":1619126756000},"page":"728","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Persistent Airway Hyperresponsiveness Following Recovery from Infection with Pneumonia Virus of Mice"],"prefix":"10.3390","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3775-838X","authenticated-orcid":false,"given":"Ajinkya R.","family":"Limkar","sequence":"first","affiliation":[{"name":"Inflammation Immunobiology Section, Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1497-8128","authenticated-orcid":false,"given":"Caroline M.","family":"Percopo","sequence":"additional","affiliation":[{"name":"Inflammation Immunobiology Section, Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jamie L.","family":"Redes","sequence":"additional","affiliation":[{"name":"Lung and Vascular Inflammation Section, Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kirk M.","family":"Druey","sequence":"additional","affiliation":[{"name":"Lung and Vascular Inflammation Section, Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Helene F.","family":"Rosenberg","sequence":"additional","affiliation":[{"name":"Inflammation Immunobiology Section, Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2021,4,22]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1393","DOI":"10.1378\/chest.128.3.1393","article-title":"One-year pulmonary function and health status in survivors of severe acute respiratory syndrome","volume":"128","author":"Ong","year":"2005","journal-title":"Chest"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"e2036142","DOI":"10.1001\/jamanetworkopen.2020.36142","article-title":"Respiratory and psychosocial sequelae among patients with COVID-19 four months after hospital discharge","volume":"4","author":"Bellan","year":"2021","journal-title":"JAMA Netw. Open"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"72","DOI":"10.1053\/spid.2002.122992","article-title":"The impact of influenza in children","volume":"13","author":"Munoz","year":"2002","journal-title":"Semin. Pediatr. Infect Dis."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"779","DOI":"10.1586\/17476348.2015.1098536","article-title":"Risk of respiratory syncytial virus infection in preterm infants: Reviewing the need for prevention","volume":"9","author":"Abraha","year":"2015","journal-title":"Expert Rev. Respir. Med."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"S184","DOI":"10.1097\/01.inf.0000188195.22502.54","article-title":"Chronic manifestations of respiratory syncytial virus infection in premature infants","volume":"24","author":"Greenough","year":"2005","journal-title":"Pediatr. Infect. Dis. J."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"895","DOI":"10.1016\/j.jaci.2017.08.003","article-title":"Role of viral infections in the development and exacerbation of asthma in children","volume":"140","author":"Jartti","year":"2017","journal-title":"Clin. Rev. Allergy Immunol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"108","DOI":"10.1164\/rccm.200603-435PP","article-title":"Bronchiolitis to asthma: A review and call for studies of gene-virus interactions in asthma causation","volume":"175","author":"Singh","year":"2007","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"513","DOI":"10.1016\/j.iac.2010.08.004","article-title":"The role of respiratory virus infections in childhood asthma inception","volume":"30","author":"Jackson","year":"2010","journal-title":"Immunol. Allergy Clin. North Am."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"633","DOI":"10.1002\/ppul.22692","article-title":"Adolescent asthma after rhinovirus and respiratory syncytial virus bronchiolitis","volume":"48","author":"Ruotsalainen","year":"2013","journal-title":"Pediatr. Pulmonol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"541","DOI":"10.1016\/S0140-6736(98)10321-5","article-title":"Respiratory syncytial virus in early life and risk of wheeze and allergy by age 13 years","volume":"354","author":"Stein","year":"1999","journal-title":"Lancet"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"811","DOI":"10.1542\/peds.2013-0982","article-title":"Effect of palivizumab prophylaxis on subsequent recurrent wheezing in preterm infants","volume":"132","author":"Yoshihara","year":"2013","journal-title":"Pediatrics"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1164\/rccm.201609-1812OC","article-title":"Palivizumab prophylaxis in preterm infants and subsequent recurrent wheezing. Six-year follow-up study","volume":"196","author":"Mochizuki","year":"2017","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"795","DOI":"10.1016\/S2213-2600(20)30109-0","article-title":"Assessing the strength of evidence for a causal effect of respiratory syncytial virus lower respiratory tract infections on subsequent wheezing illness: A systematic review and meta-analysis","volume":"8","author":"Brunwasser","year":"2020","journal-title":"Lancet Respir. Med."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"2435","DOI":"10.1016\/j.vaccine.2020.01.020","article-title":"Does respiratory syncytial virus lower respiratory illness in early life cause recurrent wheeze of early childhood and asthma? Critical review of the evidence and guidance for future studies from a World Health Organization-sponsored meeting","volume":"38","author":"Driscoll","year":"2020","journal-title":"Vaccine"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"3494","DOI":"10.3390\/v4123494","article-title":"The pneumonia virus of mice (PVM) model of acute respiratory infection","volume":"4","author":"Dyer","year":"2012","journal-title":"Viruses"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"6","DOI":"10.1016\/j.imlet.2008.03.013","article-title":"Pneumonia virus of mice: Severe respiratory infection in a natural host","volume":"118","author":"Rosenberg","year":"2008","journal-title":"Immunol. Lett."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"L148","DOI":"10.1152\/ajplung.00065.2011","article-title":"Animal models of human respiratory syncytial virus disease","volume":"301","author":"Bem","year":"2011","journal-title":"Am. J. Physiol. Lung Cell Mol. Physiol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"469","DOI":"10.1016\/j.vaccine.2016.11.054","article-title":"Animal models of respiratory syncytial virus infection","volume":"35","author":"Taylor","year":"2017","journal-title":"Vaccine"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.pharmthera.2004.09.001","article-title":"The pneumonia virus of mice infection model for severe respiratory syncytial virus infection: Identifying novel targets for therapeutic intervention","volume":"105","author":"Rosenberg","year":"2005","journal-title":"Pharmacol. Ther."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"87","DOI":"10.1016\/j.virol.2006.02.017","article-title":"Respiratory dysfunction and proinflammatory chemokines in the pneumonia virus of mice (PVM) model of viral bronchiolitis","volume":"349","author":"Bonville","year":"2006","journal-title":"Virology"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"6281","DOI":"10.1128\/JVI.00464-14","article-title":"Animal model of respiratory syncytial virus: CD8+ T cells cause a cytokine storm that is chemically tractable by sphingosine-1-phosphate 1 receptor agonist therapy","volume":"88","author":"Walsh","year":"2014","journal-title":"J. Virol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"L46","DOI":"10.1152\/ajplung.00467.2007","article-title":"Mechanical ventilation enhances lung inflammation and caspase activity in a model of mouse pneumovirus infection","volume":"296","author":"Bem","year":"2009","journal-title":"Am. J. Physiol. Lung Cell Mol. Physiol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"7984","DOI":"10.1128\/JVI.78.15.7984-7989.2004","article-title":"Functional antagonism of chemokine receptor CCR1 reduced mortality in acute pneumovirus infection in vivo","volume":"78","author":"Bonville","year":"2004","journal-title":"J. Virol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1016\/j.antiviral.2005.10.004","article-title":"Ribavirin and cysteinyl leukotriene-1 receptor blockade as treatment for severe bronchiolitis","volume":"69","author":"Bonville","year":"2006","journal-title":"Antiviral Res."},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Bondue, B., Vosters, O., de Nadai, P., Glineur, S., De Henau, O., Luangsay, S., van Gool, F., Communi, D., De Vuyst, P., and Desmecht, V. (2011). ChemR23 dampens lung inflammation and enhances anti-viral immunity in a mouse model of acute viral pneumonia. PLoS Pathog., 7.","DOI":"10.1371\/journal.ppat.1002358"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"e50385","DOI":"10.1371\/journal.pone.0050385","article-title":"Protective role of P2Y2 receptor against lung infection induced by pneumonia virus of mice","volume":"7","author":"Vanderstocken","year":"2012","journal-title":"PLoS ONE"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"871","DOI":"10.4049\/jimmunol.1800927","article-title":"Critical adverse impact of IL-6 in acute pneumovirus infection","volume":"202","author":"Percopo","year":"2019","journal-title":"J. Immunol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"131","DOI":"10.1016\/j.antiviral.2016.06.002","article-title":"Signaling via pattern recognition receptors NOD2 and TLR2 contributes to immunomodulatory control of lethal pneumovirus infection","volume":"132","author":"Rice","year":"2016","journal-title":"Antiviral Res."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"109","DOI":"10.1016\/j.antiviral.2015.07.001","article-title":"Immunobiotic Lactobacillus administered post-exposure averts the lethal sequelae of respiratory virus infection","volume":"121","author":"Percopo","year":"2015","journal-title":"Antiviral Res."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1151","DOI":"10.4049\/jimmunol.1001751","article-title":"Lactobacillus-mediated priming of the respiratory mucosa protects against lethal pneumovirus infection","volume":"186","author":"Gabryszewski","year":"2011","journal-title":"J. Immunol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"257","DOI":"10.1007\/978-1-4939-1016-8_22","article-title":"Eosinophils and respiratory virus infection: A dual-standard curve qRT-PCR-based method for determining virus recovery from mouse lung tissue","volume":"1178","author":"Percopo","year":"2014","journal-title":"Methods Mol. Biol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1085","DOI":"10.1016\/j.vaccine.2006.09.081","article-title":"Mucosal inoculation with an attenuated mouse pneumovirus strain protects against virulent challenge in wild type and interferon-gamma receptor-deficient mice","volume":"25","author":"Ellis","year":"2007","journal-title":"Vaccine"},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Mai, E., Percopo, C.M., Limkar, A.R., Sek, A.C., Ma, M., and Rosenberg, H.F. (2020). Respiratory epithelial cells respond to Lactobacillus plantarum but provide no cross-protection against virus-induced inflammation. Viruses, 13.","DOI":"10.3390\/v13010002"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"162","DOI":"10.1186\/s12931-019-1131-x","article-title":"Use of precision-cut lung slices as a translational model for the study of lung biology","volume":"20","author":"Liu","year":"2019","journal-title":"Respir. Res."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"72","DOI":"10.1186\/s12931-019-1034-x","article-title":"A. Salicylic acid amplifies carbachol-induced bronchoconstriction in human precision-cut lung slides","volume":"20","author":"Jude","year":"2019","journal-title":"Respir. Res."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"411S","DOI":"10.1378\/chest.123.3_suppl.411S","article-title":"Airway hyperresponsiveness","volume":"123","author":"Inman","year":"2003","journal-title":"Chest"},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Fang, L., Sun, Q., and Roth, M. (2020). Immunologic and non-immunologic mechanisms leading to airway remodeling in asthma. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21030757"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1585","DOI":"10.4187\/respcare.07294","article-title":"Variation among spirometry interpretation algorithms","volume":"65","author":"Mok","year":"2020","journal-title":"Respir. Care"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"190","DOI":"10.3389\/fphar.2014.00190","article-title":"Measurement of airway function using invasive and non-invasive methods in mild and severe models for allergy airway inflammation in mice","volume":"5","author":"Verheijden","year":"2014","journal-title":"Front. Pharmacol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"16","DOI":"10.1016\/j.vascn.2006.04.006","article-title":"Invasive and noninvasive lung function measurements in rodents","volume":"55","author":"Hoymann","year":"2007","journal-title":"J. Pharmacol. Toxicol. Methods"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"190","DOI":"10.1016\/j.resp.2008.06.011","article-title":"Acute influenza A infection-induced bronchial hyper-responsiveness in mice","volume":"162","author":"Bozanich","year":"2008","journal-title":"Respir. Physiol. Neurobiol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"S159","DOI":"10.1097\/01.inf.0000188155.46381.15","article-title":"Virus-induced airway dysfunction: Pathogenesis and biomechanisms","volume":"24","author":"Dakhama","year":"2005","journal-title":"Pediatr. Infect. Dis. J."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"S189","DOI":"10.1097\/01.inf.0000188196.87969.9a","article-title":"Respiratory syncytial virus infections: Old challenges and new opportunities","volume":"24","author":"Jafri","year":"2005","journal-title":"Pediatr. Infect. Dis. J."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"269","DOI":"10.1086\/514208","article-title":"Respiratory syncytial virus affects pulmonary function in BALB\/c mice","volume":"177","author":"Enhorning","year":"1998","journal-title":"J. Infect. Dis."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"91","DOI":"10.1186\/s12931-015-0244-0","article-title":"Building a better neonatal mouse model to understand infant respiratory syncytial virus disease","volume":"16","author":"You","year":"2015","journal-title":"Respir. Res."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"1435","DOI":"10.1086\/592714","article-title":"Respiratory syncytial virus persistence in the lungs correlates with airway hyperreactivity in the mouse model","volume":"198","author":"Estripeaut","year":"2008","journal-title":"J. Infect. Dis."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"1447","DOI":"10.1016\/j.jaci.2017.10.049","article-title":"Nasopharyngeal Lactobacillus is associated with a reduced risk of childhood wheezing illnesses following acute respiratory syncytial virus infection in infancy","volume":"142","author":"Shilts","year":"2018","journal-title":"J. Allergy Clin. Immunol."},{"key":"ref_48","doi-asserted-by":"crossref","unstructured":"Tomosada, Y., Chiba, E., Zelaya, H., Takahashi, T., Tsukida, K., Kitazawa, H., Alvarez, S., and Villena, J. (2013). Nasally administered Lactobacillus rhamnosus strains differentially modulate respiratory antiviral immune responses and induced protection against respiratory syncytial virus infection. BMC Immunol., 14.","DOI":"10.1186\/1471-2172-14-40"},{"key":"ref_49","doi-asserted-by":"crossref","unstructured":"Park, M.K., Ngo, V., Kwon, Y.M., Lee, Y.T., Yoo, S., Cho, Y.H., Hong, S.M., Hwang, H.S., Ko, E.J., and Jung, Y.J. (2013). Lactobacillus plantarum DK119 as a probiotic confers protection against influenza virus by modulating innate immunity. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0075368"}],"container-title":["Viruses"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1999-4915\/13\/5\/728\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T05:51:16Z","timestamp":1760161876000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1999-4915\/13\/5\/728"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,4,22]]},"references-count":49,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2021,5]]}},"alternative-id":["v13050728"],"URL":"https:\/\/doi.org\/10.3390\/v13050728","relation":{},"ISSN":["1999-4915"],"issn-type":[{"value":"1999-4915","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,4,22]]}}}