{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,29]],"date-time":"2026-03-29T14:37:39Z","timestamp":1774795059640,"version":"3.50.1"},"reference-count":43,"publisher":"Public Library of Science (PLoS)","issue":"4","license":[{"start":{"date-parts":[[2021,4,29]],"date-time":"2021-04-29T00:00:00Z","timestamp":1619654400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"FBRI SRC VB \u201cVector\u201d, Rospotrebnadzor","award":["1\/16, 2\/18 and 2\/21"],"award-info":[{"award-number":["1\/16, 2\/18 and 2\/21"]}]}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS ONE"],"abstract":"<jats:p>Outbreaks of influenza, which is a contagious respiratory disease, occur throughout the world annually, affecting millions of people with many fatal cases. The D222G\/N mutations in the hemagglutinin (HA) gene of A(H1N1)pdm09 are associated with severe and fatal human influenza cases. These mutations lead to increased virus replication in the lower respiratory tract (LRT) and may result in life-threatening pneumonia. Targeted NGS analysis revealed the presence of mutations in major and minor variants in 57% of fatal cases, with the proportion of viral variants with mutations varying from 1% to 98% in each individual sample in the epidemic season 2018\u20132019 in Russia. Co-occurrence of the mutations D222G and D222N was detected in a substantial number of the studied fatal cases (41%). The D222G\/N mutations were detected at a low frequency (less than 1%) in the rest of the studied samples from fatal and nonfatal cases of influenza. The presence of HA D222Y\/V\/A mutations was detected in a few fatal cases. The high rate of occurrence of HA D222G\/N mutations in A(H1N1)pdm09 viruses, their increased ability to replicate in the LRT and their association with fatal outcomes points to the importance of monitoring the mutations in circulating A(H1N1)pdm09 viruses for the evaluation of their epidemiological significance and for the consideration of disease prevention and treatment options.<\/jats:p>","DOI":"10.1371\/journal.pone.0251019","type":"journal-article","created":{"date-parts":[[2021,4,29]],"date-time":"2021-04-29T17:45:26Z","timestamp":1619718326000},"page":"e0251019","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":8,"title":["Evaluation of HA-D222G\/N polymorphism using targeted NGS analysis in A(H1N1)pdm09 influenza virus in Russia in 2018\u20132019"],"prefix":"10.1371","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3214-2794","authenticated-orcid":true,"given":"Alexey V.","family":"Danilenko","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Natalia P.","family":"Kolosova","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6890-1575","authenticated-orcid":true,"given":"Alexander N.","family":"Shvalov","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2354-7688","authenticated-orcid":true,"given":"Tatyana N.","family":"Ilyicheva","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Svetlana V.","family":"Svyatchenko","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alexander G.","family":"Durymanov","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Julia A.","family":"Bulanovich","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Natalia I.","family":"Goncharova","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ivan M.","family":"Susloparov","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Vasiliy Y.","family":"Marchenko","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tatyana V.","family":"Tregubchak","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Elena V.","family":"Gavrilova","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rinat A.","family":"Maksyutov","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alexander B.","family":"Ryzhikov","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"340","published-online":{"date-parts":[[2021,4,29]]},"reference":[{"key":"pone.0251019.ref001","doi-asserted-by":"crossref","DOI":"10.1093\/oso\/9780198545996.001.0001","volume-title":"Infectious Diseases of Humans: Dynamics and Control","author":"R. M. Anderson","year":"1991"},{"key":"pone.0251019.ref002","doi-asserted-by":"crossref","first-page":"D59","DOI":"10.1016\/j.vaccine.2008.07.025","article-title":"Pathology of human influenza revisited","volume":"26","author":"T Kuiken","year":"2008","journal-title":"Vaccine"},{"key":"pone.0251019.ref003","doi-asserted-by":"crossref","first-page":"102433","DOI":"10.1016\/j.jaut.2020.102433","article-title":"The epidemiology and pathogenesis of coronavirus disease (COVID-19) outbreak","volume":"109","author":"HA Rothan","year":"2020","journal-title":"J Autoimmun"},{"issue":"12","key":"pone.0251019.ref004","doi-asserted-by":"crossref","first-page":"e0194","DOI":"10.1097\/MD.0000000000010194","article-title":"Comparison of patients with avian influenza A (H7N9) and influenza A (H1N1) complicated by acute respiratory distress syndrome","volume":"97","author":"H Li","year":"2018","journal-title":"Medicine (Baltimore)"},{"issue":"7083","key":"pone.0251019.ref005","doi-asserted-by":"crossref","first-page":"435","DOI":"10.1038\/440435a","article-title":"Avian flu: influenza virus receptors in the human airway","volume":"440","author":"K Shinya","year":"2006","journal-title":"Nature"},{"issue":"1","key":"pone.0251019.ref006","doi-asserted-by":"crossref","first-page":"152","DOI":"10.1128\/MR.56.1.152-179.1992","article-title":"Evolution and ecology of influenza A viruses","volume":"56","author":"RG Webster","year":"1992","journal-title":"Microbiol Rev"},{"issue":"5","key":"pone.0251019.ref007","doi-asserted-by":"crossref","first-page":"1143","DOI":"10.1016\/j.jmb.2005.11.002","article-title":"Glycan Microarray Analysis of the Hemagglutinins from Modern and Pandemic Influenza Viruses Reveals Different Receptor Specificities","volume":"355","author":"J Stevens","year":"2006","journal-title":"J Mol Biol"},{"issue":"2","key":"pone.0251019.ref008","doi-asserted-by":"crossref","first-page":"e57059","DOI":"10.1371\/journal.pone.0057059","article-title":"Predominance of HA-222D\/G polymorphism in influenza A(H1N1)pdm09 viruses associated with fatal and severe outcomes recently circulating in Germany","volume":"8","author":"M Wedde","year":"2013","journal-title":"PLoS One"},{"issue":"7","key":"pone.0251019.ref009","doi-asserted-by":"crossref","first-page":"668","DOI":"10.1111\/j.1469-0691.2012.03984.x","article-title":"Detection of haemagglutinin D222 polymorphisms in influenza A(H1N1)pdm09-infected patients by ultra-deep pyrosequencing","volume":"19","author":"M Selleri","year":"2013","journal-title":"Clin Microbiol Infect"},{"issue":"1","key":"pone.0251019.ref010","first-page":"86","article-title":"The origin and virulence of the 1918 \u201cSpanish\u201d influenza virus","volume":"150","author":"JK Taubenberger","year":"2006","journal-title":"Proc Am Philos Soc"},{"issue":"22","key":"pone.0251019.ref011","doi-asserted-by":"crossref","first-page":"11802","DOI":"10.1128\/JVI.01136-10","article-title":"Virulence-associated substitution D222G in the hemagglutinin of 2009 pandemic influenza A(H1N1) virus affects receptor binding","volume":"84","author":"S Chutinimitkul","year":"2010","journal-title":"Am J Virol"},{"issue":"10","key":"pone.0251019.ref012","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1371\/journal.pone.0165332","article-title":"Fatal Cases of Seasonal Influenza in Russia in 2015\u20132016","volume":"11","author":"T Ilyicheva","year":"2016","journal-title":"PLoS One"},{"issue":"7","key":"pone.0251019.ref013","doi-asserted-by":"crossref","first-page":"e0220401","DOI":"10.1371\/journal.pone.0220401","article-title":"Severe cases of seasonal influenza in Russia in 2017\u20132018.","volume":"14","author":"NP Kolosova","year":"2019","journal-title":"PLoS One"},{"issue":"9","key":"pone.0251019.ref014","doi-asserted-by":"crossref","first-page":"2045","DOI":"10.1007\/s00705-020-04699-z","article-title":"Severe cases of seasonal influenza and detection of seasonal A(H1N2) in Russia in 2018\u20132019","volume":"165","author":"NP Kolosova","year":"2020","journal-title":"Arch Virol"},{"key":"pone.0251019.ref015","doi-asserted-by":"crossref","first-page":"166","DOI":"10.18821\/0507-4088-2016-61-4-166-171","article-title":"Amino acid polymorphism at residue 222 of the receptor-binding site of the hemagglutinin of the pandemic influenza a(H1N1)pdm09 from patients with lethal virus pneumonia in 2012","volume":"61","author":"K Krasnoslobodtsev","year":"2016","journal-title":"Problems of virology"},{"issue":"6","key":"pone.0251019.ref016","doi-asserted-by":"crossref","first-page":"e0178926","DOI":"10.1371\/journal.pone.0178926","article-title":"Frequency of respiratory virus infections and next-generation analysis of influenza A\/H1N1pdm09 dynamics in the lower respiratory tract of patients admitted to the ICU","volume":"12","author":"A Piralla","year":"2017","journal-title":"PLoS One"},{"key":"pone.0251019.ref017","volume-title":"Manual for the laboratory diagnosis and virological surveillance of influenza","author":"Wenqing Zhang","year":"2011"},{"key":"pone.0251019.ref018","doi-asserted-by":"crossref","unstructured":"George K St. Diagnosis of Influenza Virus. In: Yoshihiro Kawaoka, Gabriele Neumann, editors. Influenza Virus Methods and Protocols; 2012. pp. 53\u201371.","DOI":"10.1007\/978-1-61779-621-0_4"},{"key":"pone.0251019.ref019","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1016\/j.jcv.2015.04.019","article-title":"A simplified Sanger sequencing method for full genome sequencing of multiple subtypes of human influenza A viruses","volume":"68","author":"Y-M Deng","year":"2015","journal-title":"J Clin Virol"},{"issue":"12","key":"pone.0251019.ref020","doi-asserted-by":"crossref","first-page":"2275","DOI":"10.1007\/s007050170002","article-title":"Universal primer set for the full-length amplification of all influenza A viruses","volume":"146","author":"E Hoffmann","year":"2001","journal-title":"Arch Virol"},{"key":"pone.0251019.ref021","article-title":"Aligning sequence reads, clone sequences and assembly contigs with BWA-MEM","author":"H. Li","year":"2013","journal-title":"arXiv: 1303.3997v2"},{"key":"pone.0251019.ref022","unstructured":"Geneva: World Health Organization. Influenza (Seasonal). 2018 Nov 6 [cited 1 March 2021]. Available from: https:\/\/www.who.int\/en\/news-room\/fact-sheets\/detail\/influenza-(seasonal)."},{"issue":"1","key":"pone.0251019.ref023","doi-asserted-by":"crossref","first-page":"e2","DOI":"10.1093\/nar\/gkr861","article-title":"Ultrasensitive detection of rare mutations using next-generation targeted resequencing","volume":"40","author":"P Flaherty","year":"2012","journal-title":"Nucleic Acids Res"},{"issue":"8","key":"pone.0251019.ref024","first-page":"1","article-title":"Functional Balance between the Hemagglutinin and Neuraminidase of Influenza A(H1N1)pdm09 HA D222 Variants","volume":"9","author":"J-S Casalegno","year":"2014","journal-title":"PLoS One"},{"issue":"9","key":"pone.0251019.ref025","doi-asserted-by":"crossref","first-page":"e25091","DOI":"10.1371\/journal.pone.0025091","article-title":"Effect of D222G mutation in the hemagglutinin protein on receptor binding, pathogenesis and transmissibility of the 2009 pandemic H1N1 influenza virus","volume":"6","author":"JA Belser","year":"2011","journal-title":"PLoS One"},{"key":"pone.0251019.ref026","doi-asserted-by":"crossref","first-page":"79","DOI":"10.1016\/j.virusres.2014.05.001","article-title":"Hemagglutinin mutation D222N of the 2009 pandemic H1N1 influenza virus alters receptor specificity without affecting virulence in mice","volume":"189","author":"W Kong","year":"2014","journal-title":"Virus Res"},{"issue":"8","key":"pone.0251019.ref027","doi-asserted-by":"crossref","first-page":"981","DOI":"10.1258\/ebm.2010.010071","article-title":"D225G mutation in hemagglutinin of pandemic influenza H1N1 (2009) virus enhances virulence in mice","volume":"235","author":"B Zheng","year":"2010","journal-title":"Exp Biol Med (Maywood)"},{"issue":"1","key":"pone.0251019.ref028","doi-asserted-by":"crossref","first-page":"325","DOI":"10.1186\/1743-422X-7-325","article-title":"A single-amino-acid substitution in the HA protein changes the replication and pathogenicity of the 2009 pandemic A (H1N1) influenza viruses in vitro and in vivo","volume":"7","author":"L Xu","year":"2010","journal-title":"Virol J"},{"issue":"2","key":"pone.0251019.ref029","doi-asserted-by":"crossref","first-page":"e30946","DOI":"10.1371\/journal.pone.0030946","article-title":"Frequency of D222G and Q223R hemagglutinin mutants of pandemic (H1N1) 2009 influenza virus in Japan between 2009 and 2010","volume":"7","author":"M Yasugi","year":"2012","journal-title":"PLoS One"},{"key":"pone.0251019.ref030","article-title":"Observed association between the HA1 mutation D222G in the 2009 pandemic influenza A(H1N1) virus and severe clinical outcome, Norway 2009\u20132010","author":"A Kilander","year":"2010","journal-title":"Euro Surveill"},{"issue":"12","key":"pone.0251019.ref031","doi-asserted-by":"crossref","first-page":"e28332","DOI":"10.1371\/journal.pone.0028332","article-title":"Segregation of virulent influenza A(H1N1) variants in the lower respiratory tract of critically ill patients during the 2010\u20132011 seasonal epidemic","volume":"6","author":"A Piralla","year":"2011","journal-title":"PLoS One"},{"issue":"8","key":"pone.0251019.ref032","doi-asserted-by":"crossref","first-page":"1166","DOI":"10.1111\/j.1469-0691.2010.03403.x","article-title":"Severe outcome of influenza A\/H1N1\/09v infection associated with 222G\/N polymorphisms in the haemagglutinin: a multicentre study","volume":"17","author":"F Baldanti","year":"2011","journal-title":"Clin Microbiol Infect"},{"issue":"22","key":"pone.0251019.ref033","doi-asserted-by":"crossref","first-page":"12069","DOI":"10.1128\/JVI.01639-10","article-title":"Altered receptor specificity and cell tropism of D222G hemagglutinin mutants isolated from fatal cases of pandemic A(H1N1) 2009 influenza virus","volume":"84","author":"Y Liu","year":"2010","journal-title":"J Virol"},{"issue":"3","key":"pone.0251019.ref034","doi-asserted-by":"crossref","first-page":"405","DOI":"10.1002\/jmv.23295","article-title":"Clinical and molecular characteristics of the 2009 pandemic influenza H1N1 infection with severe or fatal disease from 2009 to 2011 in Shenzhen, China","volume":"85","author":"C Wu","year":"2013","journal-title":"J Med Virol"},{"issue":"12","key":"pone.0251019.ref035","doi-asserted-by":"crossref","first-page":"3167","DOI":"10.1007\/s00705-014-2179-z","article-title":"Mutations associated with severity of the pandemic influenza A(H1N1)pdm09 in humans: a systematic review and meta-analysis of epidemiological evidence","volume":"159","author":"EA Goka","year":"2014","journal-title":"Arch Virol"},{"issue":"9","key":"pone.0251019.ref036","doi-asserted-by":"crossref","first-page":"2443","DOI":"10.1093\/molbev\/msr044","article-title":"The genomic rate of molecular adaptation of the human influenza A virus","volume":"28","author":"S Bhatt","year":"2011","journal-title":"Mol Biol Evol"},{"key":"pone.0251019.ref037","article-title":"A novel twelve class fluctuation test reveals higher than expected mutation rates for influenza A viruses","author":"MD Pauly","year":"2017","journal-title":"Elife"},{"issue":"3","key":"pone.0251019.ref038","doi-asserted-by":"crossref","DOI":"10.1128\/JVI.01606-18","article-title":"Chikungunya Virus Fidelity Variants Exhibit Differential Attenuation and Population Diversity in Cell Culture and Adult Mice","volume":"93","author":"KK Riemersma","year":"2019","journal-title":"J Virol"},{"key":"pone.0251019.ref039","first-page":"21","article-title":"Preliminary review of D222G amino acid substitution in the haemagglutinin of pandemic influenza A (H1N1) 2009 viruses","volume":"85","author":"WHO, Geneva","year":"2010","journal-title":"Weekly Epidemiological Record"},{"issue":"1","key":"pone.0251019.ref040","first-page":"1","article-title":"Frequency of D222G haemagglutinin mutant of pandemic (H1N1) pdm09 influenza virus in Tunisia between 2009 and 2011","volume":"8","author":"A El Moussi","year":"2013","journal-title":"Diagn Pathol"},{"issue":"7491","key":"pone.0251019.ref041","doi-asserted-by":"crossref","first-page":"190","DOI":"10.1038\/nature12930","article-title":"Alveolar progenitor and stem cells in lung development, renewal and cancer","volume":"507","author":"TJ Desai","year":"2014","journal-title":"Nature"},{"issue":"7","key":"pone.0251019.ref042","doi-asserted-by":"crossref","first-page":"1008","DOI":"10.1093\/infdis\/jir483","article-title":"The 2009 Pandemic H1N1 D222G Hemagglutinin Mutation Alters Receptor Specificity and Increases Virulence in Mice but Not in Ferrets","volume":"204","author":"Y Abed","year":"2011","journal-title":"J Infect Dis"},{"issue":"8","key":"pone.0251019.ref043","doi-asserted-by":"crossref","DOI":"10.2807\/1560-7917.ES.2019.24.1900121","article-title":"Interim 2018\/19 influenza vaccine effectiveness: six European studies, October 2018 to January 2019","volume":"24","author":"E Kissling","year":"2019","journal-title":"Euro Surveill"}],"container-title":["PLOS ONE"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0251019","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,8,29]],"date-time":"2024-08-29T21:20:44Z","timestamp":1724966444000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0251019"}},"subtitle":[],"editor":[{"given":"Feng","family":"Wen","sequence":"first","affiliation":[],"role":[{"role":"editor","vocabulary":"crossref"}]}],"short-title":[],"issued":{"date-parts":[[2021,4,29]]},"references-count":43,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2021,4,29]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pone.0251019","relation":{},"ISSN":["1932-6203"],"issn-type":[{"value":"1932-6203","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,4,29]]}}}