{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,14]],"date-time":"2026-09-14T11:12:05Z","timestamp":1789384325753,"version":"build-2803163510"},"reference-count":40,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2014,7,24]],"date-time":"2014-07-24T00:00:00Z","timestamp":1406160000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/3.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pathogens"],"abstract":"<jats:p>Human metapneumovirus (hMPV) is the second most prevalent causative agent of pediatric respiratory infections worldwide. Currently, there are no vaccines or antiviral drugs against this virus. One of the major hurdles in hMPV research is the difficulty to identify a robust small animal model to accurately evaluate the efficacy and safety of vaccines and therapeutics. In this study, we compared the replication and pathogenesis of hMPV in BALB\/c mice, Syrian golden hamsters, and cotton rats. It was found that BALB\/c mice are not permissive for hMPV infection despite the use of a high dose  (6.5 log10 PFU) of virus for intranasal inoculation. In hamsters, hMPV replicated efficiently in nasal turbinates but demonstrated only limited replication in lungs. In cotton rats, hMPV replicated efficiently in both nasal turbinate and lung when intranasally administered with three different doses (4, 5, and 6 log10 PFU) of hMPV. Lungs of cotton rats infected by hMPV developed interstitial pneumonia with mononuclear cells infiltrates and increased lumen exudation. By immunohistochemistry, viral antigens were detected at the luminal surfaces of the bronchial epithelial cells in lungs. Vaccination of cotton rats with hMPV completely protected upper and lower respiratory tract from wildtype challenge. The immunization also elicited elevated serum neutralizing antibody. Collectively, these results demonstrated that cotton rat is a robust small animal model for hMPV infection.<\/jats:p>","DOI":"10.3390\/pathogens3030633","type":"journal-article","created":{"date-parts":[[2014,7,24]],"date-time":"2014-07-24T05:07:49Z","timestamp":1406178469000},"page":"633-655","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":20,"title":["Small Animal Models for Human Metapneumovirus: Cotton Rat is More Permissive than Hamster and Mouse"],"prefix":"10.3390","volume":"3","author":[{"given":"Yu","family":"Zhang","sequence":"first","affiliation":[{"name":"Department of Veterinary Biosciences, College of Veterinary Medicine, The Ohio State University, Columbus, OH 43210, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefan","family":"Niewiesk","sequence":"additional","affiliation":[{"name":"Department of Veterinary Biosciences, College of Veterinary Medicine, The Ohio State University, Columbus, OH 43210, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jianrong","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Veterinary Biosciences, College of Veterinary Medicine, The Ohio State University, Columbus, OH 43210, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2014,7,24]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"719","DOI":"10.1038\/89098","article-title":"A newly discovered human pneumovirus isolated from young children with respiratory tract disease","volume":"7","author":"Groen","year":"2001","journal-title":"Nat. Med."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"634","DOI":"10.3201\/eid0906.030017","article-title":"Human metapneumovirus infections in hospitalized children","volume":"9","author":"Boivin","year":"2003","journal-title":"Emerg. Infect. Dis."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"2933","DOI":"10.1099\/vir.0.2008\/006957-0","article-title":"Evolutionary dynamics of human and avian metapneumoviruses","volume":"89","author":"Osterhaus","year":"2008","journal-title":"J. Gen. Virol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1407","DOI":"10.1542\/peds.111.6.1407","article-title":"Human metapneumovirus infection in the united states: Clinical manifestations associated with a newly emerging respiratory infection in children","volume":"111","author":"Esper","year":"2003","journal-title":"Pediatrics"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1571","DOI":"10.1086\/379200","article-title":"Prevalence and clinical symptoms of human metapneumovirus infection in hospitalized patients","volume":"188","author":"Fockens","year":"2003","journal-title":"J. Infect. Dis."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"443","DOI":"10.1056\/NEJMoa025472","article-title":"Human metapneumovirus and lower respiratory tract disease in otherwise healthy infants and children","volume":"350","author":"Williams","year":"2004","journal-title":"N. Engl. J. Med."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1330","DOI":"10.1086\/344319","article-title":"Virological features and clinical manifestations associated with human metapneumovirus: A new paramyxovirus responsible for acute respiratory-tract infections in all age groups","volume":"186","author":"Boivin","year":"2002","journal-title":"J. Infect. Dis."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1660","DOI":"10.1086\/340518","article-title":"Characterization of human metapneumoviruses isolated from patients in north america","volume":"185","author":"Peret","year":"2002","journal-title":"J. Infect. Dis."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"7444","DOI":"10.1128\/jvi.66.12.7444-7451.1992","article-title":"Pulmonary histopathology induced by respiratory syncytial virus (RSV) challenge of formalin-inactivated RSV-immunized BALB\/c mice is abrogated by depletion of CD4+ T cells","volume":"66","author":"Connors","year":"1992","journal-title":"J. Virol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"2032","DOI":"10.4049\/jimmunol.151.4.2032","article-title":"Priming immunization determines t helper cytokine mrna expression patterns in lungs of mice challenged with respiratory syncytial virus","volume":"151","author":"Graham","year":"1993","journal-title":"J. Immunol."},{"key":"ref_11","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_12","doi-asserted-by":"crossref","first-page":"14003","DOI":"10.1128\/JVI.78.24.14003-14011.2004","article-title":"Human metapneumovirus persists in balb\/c mice despite the presence of neutralizing antibodies","volume":"78","author":"Alvarez","year":"2004","journal-title":"J. Virol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"8894","DOI":"10.1128\/JVI.79.14.8894-8903.2005","article-title":"Pathogenesis of human metapneumovirus lung infection in balb\/c mice and cotton rats","volume":"79","author":"Hamelin","year":"2005","journal-title":"J. Virol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1655","DOI":"10.1099\/vir.0.79805-0","article-title":"Identification of small-animal and primate models for evaluation of vaccine candidates for human metapneumovirus (hmpv) and implications for hmpv vaccine design","volume":"85","author":"MacPhail","year":"2004","journal-title":"J. Gen. Virol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"10944","DOI":"10.1128\/JVI.79.17.10944-10951.2005","article-title":"The cotton rat (Sigmodon hispidus) is a permissive small animal model of human metapneumovirus infection, pathogenesis, and protective immunity","volume":"79","author":"Williams","year":"2005","journal-title":"J. Virol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1374","DOI":"10.1128\/JVI.73.2.1374-1381.1999","article-title":"Identification of mutations contributing to the temperature-sensitive, cold-adapted, and attenuation phenotypes of the live-attenuated cold-passage 45 (cp45) human parainfluenza virus 3 candidate vaccine","volume":"73","author":"Skiadopoulos","year":"1999","journal-title":"J. Virol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1100","DOI":"10.1016\/S0264-410X(98)00327-2","article-title":"A live attenuated chimeric recombinant parainfluenza virus (piv) encoding the internal proteins of piv type 3 and the surface glycoproteins of piv type 1 induces complete resistance to piv1 challenge and partial resistance to piv3 challenge","volume":"17","author":"Tao","year":"1999","journal-title":"Vaccine"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"10678","DOI":"10.1128\/JVI.79.16.10678-10689.2005","article-title":"An s101p substitution in the putative cleavage motif of the human metapneumovirus fusion protein is a major determinant for trypsin-independent growth in vero cells and does not alter tissue tropism in hamsters","volume":"79","author":"Schickli","year":"2005","journal-title":"J. Virol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"5798","DOI":"10.1128\/JVI.00294-06","article-title":"Modification of the trypsin-dependent cleavage activation site of the human metapneumovirus fusion protein to be trypsin independent does not increase replication or spread in rodents or nonhuman primates","volume":"80","author":"Biacchesi","year":"2006","journal-title":"J. Virol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"6588","DOI":"10.1128\/JVI.79.11.6588-6597.2005","article-title":"Deletion of M2 gene open reading frames 1 and 2 of human metapneumovirus: Effects on RNA synthesis, attenuation, and immunogenicity","volume":"79","author":"Buchholz","year":"2005","journal-title":"J. Virol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"2702","DOI":"10.1099\/vir.0.83084-0","article-title":"Immunization of syrian golden hamsters with f subunit vaccine of human metapneumovirus induces protection against challenge with homologous or heterologous strains","volume":"88","author":"Herfst","year":"2007","journal-title":"J. Gen. Virol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"170","DOI":"10.1038\/laban.188","article-title":"The cotton rat (Sigmodon hispidus) as an animal model for respiratory tract infections with human pathogens","volume":"42","author":"Green","year":"2013","journal-title":"Lab Anim."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"7214","DOI":"10.1128\/jvi.71.10.7214-7219.1997","article-title":"Measles virus-induced immune suppression in the cotton rat (Sigmodon hispidus) model depends on viral glycoproteins","volume":"71","author":"Niewiesk","year":"1997","journal-title":"J. Virol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"2881","DOI":"10.1099\/0022-1317-82-12-2881","article-title":"Vaccine-enhanced respiratory syncytial virus disease in cotton rats following immunization with lot 100 or a newly prepared reference vaccine","volume":"82","author":"Prince","year":"2001","journal-title":"J. Gen. Virol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1128\/iai.42.1.81-87.1983","article-title":"Mechanisms of immunity to respiratory syncytial virus in cotton rats","volume":"42","author":"Prince","year":"1983","journal-title":"Infect. Immun."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1713","DOI":"10.1086\/345834","article-title":"A cotton rat model of human parainfluenza 3 laryngotracheitis: Virus growth, pathology, and therapy","volume":"186","author":"Ottolini","year":"2002","journal-title":"J. Infect. Dis."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1128\/jvi.65.1.103-111.1991","article-title":"Pathogenesis of human parainfluenza virus 3 infection in two species of cotton rats: Sigmodon hispidus develops bronchiolitis, while sigmodon fulviventer develops interstitial pneumonia","volume":"65","author":"Porter","year":"1991","journal-title":"J. Virol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1016\/j.antiviral.2004.12.009","article-title":"Development of a cotton rat-human metapneumovirus (hmpv) model for identifying and evaluating potential hmpv antivirals and vaccines","volume":"66","author":"Wyde","year":"2005","journal-title":"Antivir. Res."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"698","DOI":"10.1128\/JVI.00844-06","article-title":"Human metapneumovirus fusion protein vaccines that are immunogenic and protective in cotton rats","volume":"81","author":"Cseke","year":"2007","journal-title":"J. Virol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"11410","DOI":"10.1128\/JVI.01688-08","article-title":"An alphavirus replicon-based human metapneumovirus vaccine is immunogenic and protective in mice and cotton rats","volume":"82","author":"Mok","year":"2008","journal-title":"J. Virol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"8264","DOI":"10.1128\/JVI.78.15.8264-8270.2004","article-title":"Recovery of human metapneumovirus genetic lineages a and b from cloned cdna","volume":"78","author":"Herfst","year":"2004","journal-title":"J. Virol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"74","DOI":"10.1128\/JVI.74.1.74-82.2000","article-title":"Respiratory syncytial virus that lacks open reading frame 2 of the M2 gene (M2-2) has altered growth characteristics and is attenuated in rodents","volume":"74","author":"Jin","year":"2000","journal-title":"J. Virol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"11626","DOI":"10.1128\/JVI.74.24.11626-11635.2000","article-title":"Expression of the surface glycoproteins of human parainfluenza virus type 3 by bovine parainfluenza virus type 3, a novel attenuated virus vaccine vector","volume":"74","author":"Haller","year":"2000","journal-title":"J. Virol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"152","DOI":"10.1016\/j.biologicals.2009.02.017","article-title":"The cotton rat model of respiratory viral infections","volume":"37","author":"Boukhvalova","year":"2009","journal-title":"Biologicals"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"8315","DOI":"10.1128\/JVI.00106-07","article-title":"A recombinant human monoclonal antibody to human metapneumovirus fusion protein that neutralizes virus in vitro and is effective therapeutically in vivo","volume":"81","author":"Williams","year":"2007","journal-title":"J. Virol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"721","DOI":"10.1128\/jvi.57.3.721-728.1986","article-title":"Enhancement of respiratory syncytial virus pulmonary pathology in cotton rats by prior intramuscular inoculation of formalin-inactiva ted virus","volume":"57","author":"Prince","year":"1986","journal-title":"J. Virol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"5034","DOI":"10.1016\/j.vaccine.2007.04.075","article-title":"Human metapneumovirus: Enhanced pulmonary disease in cotton rats immunized with formalin-inactivated virus vaccine and challenged","volume":"25","author":"Yim","year":"2007","journal-title":"Vaccine"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"231","DOI":"10.1089\/vim.2000.13.231","article-title":"Enhanced pulmonary pathology in cotton rats upon challenge after immunization with inactivated parainfluenza virus 3 vaccines","volume":"13","author":"Ottolini","year":"2000","journal-title":"Viral Immunol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1893","DOI":"10.1016\/S0002-9440(10)63750-9","article-title":"Experimental human metapneumovirus infection of cynomolgus macaques (Macaca fascicularis) results in virus replication in ciliated epithelial cells and pneumocytes with associated lesions throughout the respiratory tract","volume":"164","author":"Kuiken","year":"2004","journal-title":"Am. J. Pathol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1016\/j.jviromet.2012.05.030","article-title":"Development and optimization of a direct plaque assay for human and avian metapneumoviruses","volume":"185","author":"Zhang","year":"2012","journal-title":"J. Virol. Method."}],"container-title":["Pathogens"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2076-0817\/3\/3\/633\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T21:14:00Z","timestamp":1760217240000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2076-0817\/3\/3\/633"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2014,7,24]]},"references-count":40,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2014,9]]}},"alternative-id":["pathogens3030633"],"URL":"https:\/\/doi.org\/10.3390\/pathogens3030633","relation":{},"ISSN":["2076-0817"],"issn-type":[{"value":"2076-0817","type":"electronic"}],"subject":[],"published":{"date-parts":[[2014,7,24]]}}}