{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,27]],"date-time":"2026-03-27T03:17:06Z","timestamp":1774581426950,"version":"3.50.1"},"reference-count":54,"publisher":"Oxford University Press (OUP)","issue":"10","license":[{"start":{"date-parts":[[2025,9,10]],"date-time":"2025-09-10T00:00:00Z","timestamp":1757462400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2025,10,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Human parainfluenza virus 2 (HPIV-2) and human parainfluenza virus 4 (HPIV-4) are significant but underappreciated respiratory pathogens, particularly among high-risk populations including children, the elderly, and immunocompromised individuals. In this study, we sequenced 101 HPIV-2 and HPIV-4 genomes from respiratory samples collected in western Washington State and performed comprehensive evolutionary analyses using both new and publicly available sequences. Phylogenetic and phylodynamic analyses revealed that both HPIV-2 and HPIV-4 evolve at significantly faster rates compared to the mumps virus, a reference human orthorubulavirus. Notably, while HPIV-2 demonstrated the highest evolutionary rates in the surface glycoprotein HN, consistent with humoral immune-driven selection, the innate immune antagonist V\/P gene evolved fastest in HPIV-4. We identified a hypervariable region within the HPIV-4V\/P protein (residues 35 to 75), which structural modeling placed in a loop overlapping a known interferon antagonism domain in other paramyxovirus V proteins, though HPIV-4 is functionally incompetent in this activity. Expanded phylogenetic analysis across the Paramyxoviridae family uncovered a striking evolutionary discordance: while the HN glycoprotein and L polymerase of HPIV-4 and its 2 closest bat-derived viruses clustered within the Orthorubulavirus genus, their nucleoprotein (N), phosphoprotein (P), matrix (M), and fusion (F) proteins formed a distinct lineage outside the Rubulavirinae subfamily. Together, these findings highlight the distinct evolutionary trajectories of HPIV-2 and HPIV-4, raise hypotheses around complex Paramyxoviridae zoonotic events including recombination-like patterns, and demonstrate limitations of current L protein-based taxonomic classification schemes.<\/jats:p>","DOI":"10.1093\/molbev\/msaf217","type":"journal-article","created":{"date-parts":[[2025,9,10]],"date-time":"2025-09-10T18:21:48Z","timestamp":1757528508000},"source":"Crossref","is-referenced-by-count":1,"title":["Distinct Evolutionary Signatures of Human Parainfluenza Viruses 2 and 4 Reveal Host Antagonism Divergence and Phylogenetic Discordance"],"prefix":"10.1093","volume":"42","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7479-3064","authenticated-orcid":false,"given":"Stephanie","family":"Goya","sequence":"first","affiliation":[{"name":"Department of Laboratory Medicine and Pathology, University of Washington Medical Center , 850 Republican St. S130, Seattle, WA 98109 ,","place":["USA"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7443-0527","authenticated-orcid":false,"given":"Alexander L","family":"Greninger","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine and Pathology, University of Washington Medical Center , 850 Republican St. S130, Seattle, WA 98109 ,","place":["USA"]},{"name":"Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center , PO Box 19024, Seattle, WA 98109 ,","place":["USA"]}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2025,9,10]]},"reference":[{"key":"2025101300112256500_msaf217-B1","doi-asserted-by":"publisher","first-page":"4931","DOI":"10.1073\/pnas.1919837117","article-title":"Structure of a paramyxovirus polymerase complex reveals a unique methyltransferase-CTD conformation","volume":"117","author":"Abdella","year":"2020","journal-title":"Proc Natl Acad Sci"},{"key":"2025101300112256500_msaf217-B2","doi-asserted-by":"publisher","first-page":"e1006650","DOI":"10.1371\/journal.pcbi.1006650","article-title":"BEAST 2.5: an advanced software platform for Bayesian evolutionary analysis","volume":"15","author":"Bouckaert","year":"2019","journal-title":"PLoS Comput Biol."},{"key":"2025101300112256500_msaf217-B3","doi-asserted-by":"publisher","first-page":"357","DOI":"10.1093\/oxfordjournals.aje.a120390","article-title":"Antigenic variation among newly isolated strains of parainfluenza type 4 virus","volume":"79","author":"Canchola","year":"1964","journal-title":"Am J Epidemiol"},{"key":"2025101300112256500_msaf217-B4","doi-asserted-by":"publisher","first-page":"1433","DOI":"10.1093\/infdis\/jiac296","article-title":"Prototype pathogen approach for vaccine and monoclonal antibody development: a critical component of the NIAID plan for pandemic preparedness","volume":"227","author":"Cassetti","year":"2022","journal-title":"J Infect Dis"},{"key":"2025101300112256500_msaf217-B5","doi-asserted-by":"publisher","first-page":"384","DOI":"10.3390\/genes12030384","article-title":"Ivar, an interpretation-oriented tool to manage the update and revision of variant annotation and classification","volume":"12","author":"Castellano","year":"2021","journal-title":"Genes (Basel)"},{"key":"2025101300112256500_msaf217-B6","doi-asserted-by":"publisher","first-page":"1122","DOI":"10.1111\/irv.13012","article-title":"Human parainfluenza 2 & 4: clinical and genetic epidemiology in the UK, 2013\u20132017, reveals distinct disease features and co-circulating genomic subtypes","volume":"16","author":"Chellapuri","year":"2022","journal-title":"Influenza Other Respir Viruses"},{"key":"2025101300112256500_msaf217-B7","doi-asserted-by":"publisher","first-page":"veab028","DOI":"10.1093\/ve\/veab028","article-title":"Evolutionary history of cotranscriptional editing in the paramyxoviral phosphoprotein gene","volume":"7","author":"Douglas","year":"2021","journal-title":"Virus Evol"},{"key":"2025101300112256500_msaf217-B8","doi-asserted-by":"publisher","first-page":"796","DOI":"10.1038\/ncomms1796","article-title":"Bats host major mammalian paramyxoviruses","volume":"3","author":"Drexler","year":"2012","journal-title":"Nat Commun"},{"key":"2025101300112256500_msaf217-B9","doi-asserted-by":"publisher","first-page":"541","DOI":"10.1038\/s41598-023-50952-1","article-title":"Recombination-aware phylogenetic analysis sheds light on the evolutionary origin of SARS-CoV-2","volume":"14","author":"Esquivel Gomez","year":"2024","journal-title":"Sci Rep"},{"key":"2025101300112256500_msaf217-B10","doi-asserted-by":"publisher","first-page":"623","DOI":"10.1093\/sysbio\/syae003","article-title":"Clockor2: inferring global and local strict molecular clocks using root-to-tip regression","volume":"73","author":"Featherstone","year":"2024","journal-title":"Syst Biol"},{"key":"2025101300112256500_msaf217-B11","doi-asserted-by":"publisher","first-page":"1016","DOI":"10.1086\/507638","article-title":"Seasonal trends of human parainfluenza viral infections: United States, 1990\u20132004","volume":"43","author":"Fry","year":"2006","journal-title":"Clin Infect Dis"},{"key":"2025101300112256500_msaf217-B12","doi-asserted-by":"publisher","first-page":"177","DOI":"10.1128\/JCM.01881-16","article-title":"Rapid metagenomic next-generation sequencing during an investigation of hospital-acquired human parainfluenza virus 3 infections","volume":"55","author":"Greninger","year":"2017","journal-title":"J Clin Microbiol"},{"key":"2025101300112256500_msaf217-B13","doi-asserted-by":"publisher","first-page":"1358","DOI":"10.3390\/v3081358","article-title":"Homologous recombination in negative sense RNA viruses","volume":"3","author":"Han","year":"2011","journal-title":"Viruses"},{"key":"2025101300112256500_msaf217-B14","doi-asserted-by":"publisher","first-page":"e0093021","DOI":"10.1128\/Spectrum.00930-21","article-title":"Eptesicus fuscus orthorubulavirus, a close relative of human parainfluenza virus 4, discovered in a bat in South Dakota","volume":"9","author":"Hause","year":"2021","journal-title":"Microbiol Spectr"},{"key":"2025101300112256500_msaf217-B15","doi-asserted-by":"publisher","first-page":"518","DOI":"10.1093\/molbev\/msx281","article-title":"UFBoot2: improving the ultrafast bootstrap approximation","volume":"35","author":"Hoang","year":"2018","journal-title":"Mol Biol Evol"},{"key":"2025101300112256500_msaf217-B16","doi-asserted-by":"publisher","first-page":"3059","DOI":"10.1093\/nar\/gkf436","article-title":"MAFFT: a novel method for rapid multiple sequence alignment based on fast Fourier transform","volume":"30","author":"Katoh","year":"2002","journal-title":"Nucleic Acids Res"},{"key":"2025101300112256500_msaf217-B17","doi-asserted-by":"publisher","first-page":"321","DOI":"10.1016\/0042-6822(90)90413-L","article-title":"Sequence analysis of the phosphoprotein (P) genes of human parainfluenza type 4A and 4B viruses and RNA editing at transcript of the P genes: the number of G residues added is imprecise","volume":"178","author":"Kondo","year":"1990","journal-title":"Virology"},{"key":"2025101300112256500_msaf217-B18","doi-asserted-by":"publisher","first-page":"e01098-21","DOI":"10.1128\/jvi.01098-21","article-title":"Evolution and diversity of bat and rodent paramyxoviruses from North America","volume":"96","author":"Larsen","year":"2022","journal-title":"J Virol"},{"key":"2025101300112256500_msaf217-B19","doi-asserted-by":"publisher","first-page":"3276","DOI":"10.1093\/bioinformatics\/btu531","article-title":"AliView: a fast and lightweight alignment viewer and editor for large datasets","volume":"30","author":"Larsson","year":"2014","journal-title":"Bioinformatics"},{"key":"2025101300112256500_msaf217-B20","doi-asserted-by":"publisher","first-page":"4515","DOI":"10.1128\/JCM.43.9.4515-4521.2005","article-title":"Human parainfluenza virus 4 outbreak and the role of diagnostic tests","volume":"43","author":"Lau","year":"2005","journal-title":"J Clin Microbiol"},{"key":"2025101300112256500_msaf217-B21","doi-asserted-by":"publisher","author":"Li","year":"2013","DOI":"10.48550\/arXiv.1303.3997"},{"key":"2025101300112256500_msaf217-B22","doi-asserted-by":"publisher","first-page":"105","DOI":"10.1016\/j.cell.2005.10.033","article-title":"Structure of DDB1 in complex with a paramyxovirus V protein: viral hijack of a propeller cluster in ubiquitin ligase","volume":"124","author":"Li","year":"2006","journal-title":"Cell"},{"key":"2025101300112256500_msaf217-B23","doi-asserted-by":"publisher","first-page":"2242","DOI":"10.3201\/eid2112.141111","article-title":"Parainfluenza virus 5 as possible cause of severe respiratory disease in calves, China","volume":"21","author":"Liu","year":"2015","journal-title":"Emerg Infect Dis"},{"key":"2025101300112256500_msaf217-B24","first-page":"1","volume-title":"Advances in virus research","author":"Marcink","year":"2021"},{"key":"2025101300112256500_msaf217-B25","doi-asserted-by":"publisher","first-page":"veaa087","DOI":"10.1093\/ve\/veaa087","article-title":"RDP5: a computer program for analyzing recombination in, and removing signals of recombination from, nucleotide sequence datasets","volume":"7","author":"Martin","year":"2021","journal-title":"Virus Evol"},{"key":"2025101300112256500_msaf217-B26","doi-asserted-by":"publisher","first-page":"706","DOI":"10.1111\/irv.12597","article-title":"Seasonality and clinical impact of human parainfluenza viruses","volume":"12","author":"Maykowski","year":"2018","journal-title":"Influenza Other Respir Viruses"},{"key":"2025101300112256500_msaf217-B27","doi-asserted-by":"publisher","first-page":"1530","DOI":"10.1093\/molbev\/msaa015","article-title":"IQ-TREE 2: new models and efficient methods for phylogenetic inference in the genomic era","volume":"37","author":"Minh","year":"2020","journal-title":"Mol Biol Evol"},{"key":"2025101300112256500_msaf217-B28","doi-asserted-by":"publisher","first-page":"690","DOI":"10.1126\/science.1230949","article-title":"Paramyxovirus V proteins disrupt the fold of the RNA sensor MDA5 to inhibit antiviral signaling","volume":"339","author":"Motz","year":"2013","journal-title":"Science"},{"key":"2025101300112256500_msaf217-B29","doi-asserted-by":"publisher","first-page":"1196","DOI":"10.1093\/molbev\/mst030","article-title":"FUBAR: a Fast, Unconstrained Bayesian AppRoximation for inferring selection","volume":"30","author":"Murrell","year":"2013","journal-title":"Mol Biol Evol"},{"key":"2025101300112256500_msaf217-B30","doi-asserted-by":"publisher","first-page":"8591","DOI":"10.1128\/JVI.79.13.8591-8601.2005","article-title":"Identification of paramyxovirus V protein residues essential for STAT protein degradation and promotion of virus replication","volume":"79","author":"Nishio","year":"2005","journal-title":"J Virol"},{"key":"2025101300112256500_msaf217-B31","doi-asserted-by":"publisher","first-page":"6130","DOI":"10.1128\/JVI.02635-07","article-title":"Human parainfluenza virus type 2\u2005V protein inhibits genome replication by binding to the L protein: possible role in promoting viral fitness","volume":"82","author":"Nishio","year":"2008","journal-title":"J Virol"},{"key":"2025101300112256500_msaf217-B32","doi-asserted-by":"publisher","first-page":"2093","DOI":"10.1099\/0022-1317-71-9-2093","article-title":"Immunological relationships of simian virus 41 (SV41) to other paramyxoviruses and serological evidence of SV41 infection in human populations","volume":"71","author":"Nishio","year":"1990","journal-title":"J Gen Virol"},{"key":"2025101300112256500_msaf217-B33","doi-asserted-by":"publisher","first-page":"14756","DOI":"10.1128\/JVI.79.23.14756-14768.2005","article-title":"Human parainfluenza virus type 4 is incapable of evading the interferon-induced antiviral effect","volume":"79","author":"Nishio","year":"2005","journal-title":"J Virol"},{"key":"2025101300112256500_msaf217-B34","doi-asserted-by":"publisher","first-page":"824","DOI":"10.1101\/gr.213959.116","article-title":"metaSPAdes: a new versatile metagenomic assembler","volume":"27","author":"Nurk","year":"2017","journal-title":"Genome Res"},{"key":"2025101300112256500_msaf217-B35","doi-asserted-by":"publisher","first-page":"1508","DOI":"10.3390\/microorganisms9071508","article-title":"Virological surveillance and molecular characterization of human parainfluenzavirus infection in children with acute respiratory illness: Germany, 2015\u20132019","volume":"9","author":"Oh","year":"2021","journal-title":"Microorganisms"},{"key":"2025101300112256500_msaf217-B36","doi-asserted-by":"publisher","first-page":"6435","DOI":"10.1128\/JVI.76.13.6435-6441.2002","article-title":"STAT2 acts as a host range determinant for Species-specific paramyxovirus interferon antagonism and simian virus 5 replication","volume":"76","author":"Parisien","year":"2002","journal-title":"J Virol"},{"key":"2025101300112256500_msaf217-B37","doi-asserted-by":"publisher","first-page":"659","DOI":"10.3390\/v15030659","article-title":"Genomic characterization of a relative of mumps virus in lesser dawn bats of Southeast Asia","volume":"15","author":"Paskey","year":"2023","journal-title":"Viruses"},{"key":"2025101300112256500_msaf217-B38","doi-asserted-by":"publisher","first-page":"70","DOI":"10.1002\/pro.3943","article-title":"UCSF ChimeraX: structure visualization for researchers, educators, and developers","volume":"30","author":"Pettersen","year":"2021","journal-title":"Protein Sci"},{"key":"2025101300112256500_msaf217-B39","doi-asserted-by":"publisher","first-page":"1208","DOI":"10.1093\/molbev\/msi105","article-title":"Not so different after all: a comparison of methods for detecting amino acid sites under selection","volume":"22","author":"Pond","year":"2005","journal-title":"Mol Biol Evol"},{"key":"2025101300112256500_msaf217-B40","doi-asserted-by":"publisher","first-page":"1593","DOI":"10.1099\/jgv.0.001328","article-title":"ICTV virus taxonomy profile: Paramyxoviridae","volume":"100","author":"Rima","year":"2019","journal-title":"J Gen Virol"},{"key":"2025101300112256500_msaf217-B41","author":"Rima"},{"key":"2025101300112256500_msaf217-B42","doi-asserted-by":"publisher","first-page":"24","DOI":"10.1038\/nbt.1754","article-title":"Integrative genomics viewer","volume":"29","author":"Robinson","year":"2011","journal-title":"Nat Biotechnol"},{"key":"2025101300112256500_msaf217-B43","doi-asserted-by":"publisher","first-page":"539","DOI":"10.1093\/sysbio\/sys029","article-title":"MrBayes 3.2: efficient Bayesian phylogenetic inference and model choice across a large model space","volume":"61","author":"Ronquist","year":"2012","journal-title":"Syst Biol"},{"key":"2025101300112256500_msaf217-B44","doi-asserted-by":"publisher","first-page":"W5","DOI":"10.1093\/nar\/gkz342","article-title":"MAFFT-DASH: integrated protein sequence and structural alignment","volume":"47","author":"Rozewicki","year":"2019","journal-title":"Nucleic Acids Res"},{"key":"2025101300112256500_msaf217-B45","doi-asserted-by":"publisher","first-page":"492","DOI":"10.1080\/10635150290069913","article-title":"An approximately unbiased test of phylogenetic tree selection","volume":"51","author":"Shimodaira","year":"2002","journal-title":"Syst Biol"},{"key":"2025101300112256500_msaf217-B46","doi-asserted-by":"publisher","first-page":"236","DOI":"10.1007\/s00705-024-06143-y","article-title":"Changes to virus taxonomy and the ICTV statutes ratified by the International Committee on Taxonomy of Viruses (2024)","volume":"169","author":"Simmonds","year":"2024","journal-title":"Arch Virol"},{"key":"2025101300112256500_msaf217-B47","doi-asserted-by":"publisher","first-page":"2128","DOI":"10.1038\/s41564-024-01722-w","article-title":"Functional and structural basis of human parainfluenza virus type 3 neutralization with human monoclonal antibodies","volume":"9","author":"Suryadevara","year":"2024","journal-title":"Nat Microbiol"},{"key":"2025101300112256500_msaf217-B48","author":"Vanmechelen"},{"key":"2025101300112256500_msaf217-B49","doi-asserted-by":"publisher","first-page":"72","DOI":"10.1186\/s40168-024-01782-4","article-title":"Substantial viral diversity in bats and rodents from East Africa: insights into evolution, recombination, and cocirculation","volume":"12","author":"Wang","year":"2024","journal-title":"Microbiome"},{"key":"2025101300112256500_msaf217-B50","doi-asserted-by":"publisher","first-page":"e1077","DOI":"10.1016\/S2214-109X(21)00218-7","article-title":"Global burden of acute lower respiratory infection associated with human parainfluenza virus in children younger than 5 years for 2018: a systematic review and meta-analysis","volume":"9","author":"Wang","year":"2021","journal-title":"Lancet Glob Health"},{"key":"2025101300112256500_msaf217-B51","doi-asserted-by":"publisher","first-page":"W296","DOI":"10.1093\/nar\/gky427","article-title":"SWISS-MODEL: homology modelling of protein structures and complexes","volume":"46","author":"Waterhouse","year":"2018","journal-title":"Nucleic Acids Res"},{"key":"2025101300112256500_msaf217-B52","doi-asserted-by":"publisher","first-page":"254","DOI":"10.1016\/j.jcv.2013.03.016","article-title":"Field evaluation of TaqMan array card (TAC) for the simultaneous detection of multiple respiratory viruses in children with acute respiratory infection","volume":"57","author":"Weinberg","year":"2013","journal-title":"J Clin Virol"},{"key":"2025101300112256500_msaf217-B53","doi-asserted-by":"publisher","first-page":"26","DOI":"10.3390\/v1010026","article-title":"The complete sequence of a human parainfluenzavirus 4 genome","volume":"1","author":"Yea","year":"2009","journal-title":"Viruses"},{"key":"2025101300112256500_msaf217-B54","doi-asserted-by":"publisher","first-page":"e0343223","DOI":"10.1128\/spectrum.03432-23","article-title":"Genetic characteristics of human parainfluenza viruses 1\u20134 associated with acute lower respiratory tract infection in Chinese children","volume":"12","author":"Zhu","year":"2024","journal-title":"Microbiol Spectr"}],"container-title":["Molecular Biology and Evolution"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/mbe\/advance-article-pdf\/doi\/10.1093\/molbev\/msaf217\/64237394\/msaf217.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/mbe\/article-pdf\/42\/10\/msaf217\/64237394\/msaf217.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/mbe\/article-pdf\/42\/10\/msaf217\/64237394\/msaf217.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,13]],"date-time":"2025-10-13T04:11:30Z","timestamp":1760328690000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/mbe\/article\/doi\/10.1093\/molbev\/msaf217\/8250741"}},"subtitle":[],"editor":[{"given":"Adi","family":"Stern","sequence":"additional","affiliation":[],"role":[{"role":"editor","vocabulary":"crossref"}]}],"short-title":[],"issued":{"date-parts":[[2025,9,10]]},"references-count":54,"journal-issue":{"issue":"10","published-print":{"date-parts":[[2025,10,1]]}},"URL":"https:\/\/doi.org\/10.1093\/molbev\/msaf217","relation":{},"ISSN":["0737-4038","1537-1719"],"issn-type":[{"value":"0737-4038","type":"print"},{"value":"1537-1719","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2025,10]]},"published":{"date-parts":[[2025,9,10]]},"article-number":"msaf217"}}