{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,15]],"date-time":"2026-05-15T16:55:36Z","timestamp":1778864136723,"version":"3.51.4"},"reference-count":35,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2025,2,27]],"date-time":"2025-02-27T00:00:00Z","timestamp":1740614400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Phase III Preclinical Study of Prophylactic Human Respiratory Syncytial Virus-Surveillance of monoclonal antibody target genes of respiratory syncytial virus in China.","award":["CJ0183"],"award-info":[{"award-number":["CJ0183"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>In a previous outbreak of the human respiratory syncytial virus (HRSV), we identified a variant strain of genotype BA9 with a seven-amino-acid extension (Q-R-L-Q-S-Y-A) at the C-terminus of the attachment protein (G). To assess the impact of this extension on the virulence of HRSV, two full-length infectious clones using the wild strain of genotype BA9 as a backbone, one containing the seven-amino-acid extension (rRSV BA9 WT), and the other deleting this extension (rRSV BA9 \u03947AA), were successfully rescued using a reverse genetics system. The biological properties and virulence of the two rescued viruses were then compared and analyzed in vitro and in vivo. Compared to the rRSV BA9 \u03947AA, the rRSV BA9 WT exhibited a larger plaque size and a more pronounced suppression of the host cell innate immune response in vitro (IFN-\u03b2 levels: 154.33 pg\/mL vs. 11.27 pg\/mL). The rRSV BA9 WT demonstrated increased adaptability in mice, with a 10-fold higher lung viral load and a stronger inflammatory response following intranasal exposure. Our study primarily demonstrated that the C-terminal extension of the G protein of the HRSV can enhance viral virulence, underscoring the importance of virological surveillance in the prevention and treatment of severe HRSV-related disease.<\/jats:p>","DOI":"10.3390\/ijms26052081","type":"journal-article","created":{"date-parts":[[2025,2,27]],"date-time":"2025-02-27T03:37:57Z","timestamp":1740627477000},"page":"2081","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Enhanced Pathogenic Consequences Induced by a Seven-Amino-Acid Extension in the G Protein of the HRSV BA9 Genotype"],"prefix":"10.3390","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5864-1554","authenticated-orcid":false,"given":"Na","family":"Wang","sequence":"first","affiliation":[{"name":"National Key Laboratory of Intelligent Tracking and Forecasting for Infectious Diseases, National Institute for Viral Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing 102206, China"},{"name":"NHC Key Laboratory of Medical Virology and Viral Disease, National Institute for Viral Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing 102206, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5433-4458","authenticated-orcid":false,"given":"Jingjing","family":"Song","sequence":"additional","affiliation":[{"name":"National Key Laboratory of Intelligent Tracking and Forecasting for Infectious Diseases, National Institute for Viral Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing 102206, China"},{"name":"NHC Key Laboratory of Medical Virology and Viral Disease, National Institute for Viral Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing 102206, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lei","family":"Cao","sequence":"additional","affiliation":[{"name":"National Key Laboratory of Intelligent Tracking and Forecasting for Infectious Diseases, National Institute for Viral Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing 102206, China"},{"name":"NHC Key Laboratory of Medical Virology and Viral Disease, National Institute for Viral Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing 102206, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Naiying","family":"Mao","sequence":"additional","affiliation":[{"name":"National Key Laboratory of Intelligent Tracking and Forecasting for Infectious Diseases, National Institute for Viral Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing 102206, China"},{"name":"NHC Key Laboratory of Medical Virology and Viral Disease, National Institute for Viral Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing 102206, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yuqing","family":"Shi","sequence":"additional","affiliation":[{"name":"National Key Laboratory of Intelligent Tracking and Forecasting for Infectious Diseases, National Institute for Viral Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing 102206, China"},{"name":"NHC Key Laboratory of Medical Virology and Viral Disease, National Institute for Viral Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing 102206, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jie","family":"Jiang","sequence":"additional","affiliation":[{"name":"National Key Laboratory of Intelligent Tracking and Forecasting for Infectious Diseases, National Institute for Viral Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing 102206, China"},{"name":"NHC Key Laboratory of Medical Virology and Viral Disease, National Institute for Viral Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing 102206, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wuyang","family":"Zhu","sequence":"additional","affiliation":[{"name":"National Key Laboratory of Intelligent Tracking and Forecasting for Infectious Diseases, National Institute for Viral Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing 102206, China"},{"name":"NHC Key Laboratory of Medical Virology and Viral Disease, National Institute for Viral Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing 102206, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yan","family":"Zhang","sequence":"additional","affiliation":[{"name":"National Key Laboratory of Intelligent Tracking and Forecasting for Infectious Diseases, National Institute for Viral Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing 102206, China"},{"name":"NHC Key Laboratory of Medical Virology and Viral Disease, National Institute for Viral Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing 102206, China"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,2,27]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"18","DOI":"10.1053\/jinf.2002.1015","article-title":"Respiratory syncytial virus\u2014Viral biology and the host response","volume":"45","author":"Hacking","year":"2002","journal-title":"J. Infect."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"2047","DOI":"10.1016\/S0140-6736(22)00478-0","article-title":"Global, regional, and national disease burden estimates of acute lower respiratory infections due to respiratory syncytial virus in children younger than 5 years in 2019: A systematic analysis","volume":"399","author":"Li","year":"2022","journal-title":"Lancet"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"e28611","DOI":"10.1002\/jmv.28611","article-title":"Circulation pattern and genetic variation of human respiratory syncytial virus in China during 2008\u20132021","volume":"95","author":"Song","year":"2023","journal-title":"J. Med. Virol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"8258","DOI":"10.1128\/JVI.01045-15","article-title":"Functional Analysis of the 60-Nucleotide Duplication in the Respiratory Syncytial Virus Buenos Aires Strain Attachment Glycoprotein","volume":"89","author":"Hotard","year":"2015","journal-title":"J. Virol."},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Wang, B., Song, J., Song, J., Mao, N., Liang, J., Chen, Y., Qi, Y., Bai, L., Xie, Z., and Zhang, Y. (2022). An Outbreak of Severe Neonatal Pneumonia Caused by Human Respiratory Syncytial Virus BA9 in a Postpartum Care Centre in Shenyang, China. Microbiol. Spectr., 10.","DOI":"10.1128\/spectrum.00974-22"},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Lu, B., Liu, H., Tabor, D.E., Tovchigrechko, A., Qi, Y., Ruzin, A., Esser, M.T., and Jin, H. (2019). Emergence of new antigenic epitopes in the glycoproteins of human respiratory syncytial virus collected from a US surveillance study, 2015\u20132017. Sci. Rep., 9.","DOI":"10.1038\/s41598-019-40387-y"},{"key":"ref_7","first-page":"120","article-title":"A new variant of respiratory syncytial virus glycoprotein gene and clinical features of infected children","volume":"44","author":"Jiang","year":"2024","journal-title":"Chin. J. Microbiol. Immunol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"526","DOI":"10.1093\/infdis\/jiy496","article-title":"How Respiratory Syncytial Virus Genotypes Influence the Clinical Course in Infants Hospitalized for Bronchiolitis","volume":"219","author":"Midulla","year":"2019","journal-title":"J. Infect. Dis."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"541","DOI":"10.1128\/CMR.18.3.541-555.2005","article-title":"Immune responses and disease enhancement during respiratory syncytial virus infection","volume":"18","author":"Openshaw","year":"2005","journal-title":"Clin. Microbiol. Rev."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"e01704-14","DOI":"10.1128\/mBio.01704-14","article-title":"Refining the balance of attenuation and immunogenicity of respiratory syncytial virus by targeted codon deoptimization of virulence genes","volume":"5","author":"Meng","year":"2014","journal-title":"mBio"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1372494","DOI":"10.1155\/2020\/1372494","article-title":"Human Type I Interferon Antiviral Effects in Respiratory and Reemerging Viral Infections","volume":"2020","author":"Acosta","year":"2020","journal-title":"J. Immunol. Res."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"116","DOI":"10.1186\/1743-422X-5-116","article-title":"Respiratory syncytial virus (RSV) attachment and nonstructural proteins modify the type I interferon response associated with suppressor of cytokine signaling (SOCS) proteins and IFN-stimulated gene-15 (ISG15)","volume":"5","author":"Moore","year":"2008","journal-title":"Virol. J."},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Rivas-Fuentes, S., Salgado-Aguayo, A., Santos-Mendoza, T., and Sevilla-Reyes, E. (2024). The Role of the CX3CR1-CX3CL1 Axis in Respiratory Syncytial Virus Infection and the Triggered Immune Response. Int. J. Mol. Sci., 25.","DOI":"10.20944\/preprints202407.0855.v1"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"3409","DOI":"10.1128\/JVI.77.6.3409-3417.2003","article-title":"Strain-dependent structural variants of herpes simplex virus type 1 ICP34.5 determine viral plaque size, efficiency of glycoprotein processing, and viral release and neuroinvasive disease potential","volume":"77","author":"Mao","year":"2003","journal-title":"J. Virol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"16160","DOI":"10.1038\/s41598-017-16475-2","article-title":"Characterization of large and small-plaque variants in the Zika virus clinical isolate ZIKV\/Hu\/S36\/Chiba\/2016","volume":"7","author":"Kato","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"2710","DOI":"10.1128\/JVI.73.4.2710-2716.1999","article-title":"Mapping the genetic determinants of pathogenicity and plaque phenotype in swine vesicular disease virus","volume":"73","author":"Kanno","year":"1999","journal-title":"J. Virol."},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Tajima, S., Ebihara, H., and Lim, C.K. (2024). Amino Acids at Positions 156 and 332 in the E Protein of the West Nile Virus Subtype Kunjin Virus Classical Strain OR393 Are Involved in Plaque Size, Growth, and Pathogenicity in Mice. Viruses, 16.","DOI":"10.3390\/v16081237"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"4744","DOI":"10.1128\/JVI.75.10.4744-4751.2001","article-title":"N-glycans of F protein differentially affect fusion activity of human respiratory syncytial virus","volume":"75","author":"Zimmer","year":"2001","journal-title":"J. Virol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1128\/JVI.01201-20","article-title":"A Respiratory Syncytial Virus Attachment Gene Variant Associated with More Severe Disease in Infants Decreases Fusion Protein Expression, Which May Facilitate Immune Evasion","volume":"95","author":"Human","year":"2020","journal-title":"J. Virol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"4767","DOI":"10.1128\/jvi.63.11.4767-4776.1989","article-title":"Structure and cell surface maturation of the attachment glycoprotein of human respiratory syncytial virus in a cell line deficient in O glycosylation","volume":"63","author":"Wertz","year":"1989","journal-title":"J. Virol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"11611","DOI":"10.1128\/JVI.01726-14","article-title":"Structural insights into the human metapneumovirus glycoprotein ectodomain","volume":"88","author":"Leyrat","year":"2014","journal-title":"J. Virol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"e2026","DOI":"10.1002\/rmv.2026","article-title":"Disease severity in respiratory syncytial virus infection: Role of host genetic variation","volume":"29","author":"Tahamtan","year":"2019","journal-title":"Rev. Med. Virol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1305","DOI":"10.1164\/rccm.201002-0221OC","article-title":"Viral load drives disease in humans experimentally infected with respiratory syncytial virus","volume":"182","author":"DeVincenzo","year":"2010","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1097\/00006454-200002000-00006","article-title":"Nasal quantity of respiratory syncytical virus correlates with disease severity in hospitalized infants","volume":"19","author":"Buckingham","year":"2000","journal-title":"Pediatr. Infect. Dis. J."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1111\/j.1600-065X.2008.00698.x","article-title":"Inborn errors of interferon (IFN)-mediated immunity in humans: Insights into the respective roles of IFN-alpha\/beta, IFN-gamma, and IFN-lambda in host defense","volume":"226","author":"Zhang","year":"2008","journal-title":"Immunol. Rev."},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Schijf, M.A., Lukens, M.V., Kruijsen, D., van Uden, N.O.P., Garssen, J., Coenjaerts, F.E.J., Land, B.V., and van Bleek, G.M. (2013). Respiratory syncytial virus induced type I IFN production by pDC is regulated by RSV-infected airway epithelial cells, RSV-exposed monocytes and virus specific antibodies. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0081695"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"e00535-18","DOI":"10.1128\/mBio.00535-18","article-title":"The Efficacy of the Interferon Alpha\/Beta Response versus Arboviruses Is Temperature Dependent","volume":"9","author":"Lane","year":"2018","journal-title":"mBio"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"452","DOI":"10.1159\/000446824","article-title":"Alveolar Macrophages Can Control Respiratory Syncytial Virus Infection in the Absence of Type I Interferons","volume":"8","author":"Makris","year":"2016","journal-title":"J. Innate Immun."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"199134","DOI":"10.1016\/j.virusres.2023.199134","article-title":"SARS-CoV-2 omicron sub-lineages differentially modulate interferon response in human lung epithelial cells","volume":"332","author":"Anichini","year":"2023","journal-title":"Virus Res."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"290","DOI":"10.1134\/S0006297921030068","article-title":"Molecular and Cellular Mechanisms of Respiratory Syncytial Viral Infection: Using Murine Models to Understand Human Pathology","volume":"86","author":"Shilovskiy","year":"2021","journal-title":"Biochem. Biokhimiia"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"5068","DOI":"10.1128\/JVI.00259-16","article-title":"Respiratory Syncytial Virus (RSV) Pulmonary Infection in Humanized Mice Induces Human Anti-RSV Immune Responses and Pathology","volume":"90","author":"Lukacs","year":"2016","journal-title":"J. Virol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"977","DOI":"10.2353\/ajpath.2006.051055","article-title":"Differential immune responses and pulmonary pathophysiology are induced by two different strains of respiratory syncytial virus","volume":"169","author":"Lukacs","year":"2006","journal-title":"Am. J. Pathol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1114","DOI":"10.1097\/00006454-199812000-00003","article-title":"Severity of respiratory syncytial virus disease related to type and genotype of virus and to cytokine values in nasopharyngeal secretions","volume":"17","author":"Hornsleth","year":"1998","journal-title":"Pediatr. Infect. Dis. J."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"106","DOI":"10.1183\/09031936.03.00048103","article-title":"Pro- and anti-inflammatory responses in respiratory syncytial virus bronchiolitis","volume":"23","author":"McNamara","year":"2004","journal-title":"Eur. Respir. J."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"e437","DOI":"10.1097\/INF.0b013e3182a14407","article-title":"Novel inflammatory markers, clinical risk factors and virus type associated with severe respiratory syncytial virus infection","volume":"32","author":"Tabarani","year":"2013","journal-title":"Pediatr. Infect. Dis. J."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/5\/2081\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T16:43:10Z","timestamp":1760028190000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/5\/2081"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,2,27]]},"references-count":35,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2025,3]]}},"alternative-id":["ijms26052081"],"URL":"https:\/\/doi.org\/10.3390\/ijms26052081","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,2,27]]}}}