{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,11]],"date-time":"2026-10-11T13:39:03Z","timestamp":1791725943748,"version":"4.3.4"},"reference-count":35,"publisher":"Public Library of Science (PLoS)","issue":"1","license":[{"start":{"date-parts":[[2022,1,31]],"date-time":"2022-01-31T00:00:00Z","timestamp":1643587200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Key R&D program of China","award":["2016YFC1201000"],"award-info":[{"award-number":["2016YFC1201000"]}]},{"name":"National Key R&D program of China","award":["2016YFC1201000"],"award-info":[{"award-number":["2016YFC1201000"]}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81771688"],"award-info":[{"award-number":["81771688"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["31970878"],"award-info":[{"award-number":["31970878"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81971568"],"award-info":[{"award-number":["81971568"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003453","name":"Natural Science Foundation of Guangdong Province","doi-asserted-by":"publisher","award":["2016A030311046"],"award-info":[{"award-number":["2016A030311046"]}],"id":[{"id":"10.13039\/501100003453","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Scientific and Technological Project of Guangdong Province","award":["2017B020226006"],"award-info":[{"award-number":["2017B020226006"]}]}],"content-domain":{"domain":["www.plosntds.org"],"crossmark-restriction":false},"short-container-title":["PLoS Negl Trop Dis"],"abstract":"<jats:p>\n                    Chikungunya virus (CHIKV) is an emerging mosquito-transmitted alphavirus that leads to acute fever and chronic debilitating polyarthralgia. To date, the mechanism underlying chronic recurrent arthralgia is unknown. In the present study, newborn wild-type C57BL\/6 mice were infected with CHIKV, and the virological and pathological features of CHIKV infection were analyzed over a period of 50 days. Acute viral infection was readily established by footpad inoculation of CHIKV at doses ranging from 10 plaque forming unit (PFU) to 10\n                    <jats:sup>6<\/jats:sup>\n                    PFU, during which inoculation dose-dependent viral RNA and skeletal muscle damage were detected in the foot tissues. However, persistent CHIKV was observed only when the mice were infected with a high dose of 10\n                    <jats:sup>6<\/jats:sup>\n                    PFU of CHIKV, in which low copy numbers (10\n                    <jats:sup>3<\/jats:sup>\n                    \u221210\n                    <jats:sup>4<\/jats:sup>\n                    ) of viral positive strand RNA were continuously detectable in the feet from 29 to 50 dpi, along with a low level and progressive reduction in virus-specific CD8+ T cell responses. In contrast, viral negative strand RNA was detected at 50 dpi but not at 29 dpi and was accompanied by significant local skeletal muscle damage at 50 dpi when mild synovial hyperplasia appeared in the foot joints, although the damage was briefly repaired at 29 dpi. These results demonstrated that a high viral inoculation dose leads to viral persistence and progression to chronic tissue damage after recovery from acute infection. Taken together, these results provide a useful tool for elucidating the pathogenesis of persistent CHIKV infection and viral relapse-associated chronic arthritis.\n                  <\/jats:p>","DOI":"10.1371\/journal.pntd.0010149","type":"journal-article","created":{"date-parts":[[2022,1,31]],"date-time":"2022-01-31T13:21:51Z","timestamp":1643635311000},"page":"e0010149","update-policy":"https:\/\/doi.org\/10.1371\/journal.pntd.corrections_policy","source":"Crossref","is-referenced-by-count":17,"title":["A high-dose inoculum size results in persistent viral infection and arthritis in mice infected with chikungunya virus"],"prefix":"10.1371","volume":"16","author":[{"given":"Yue","family":"Zhang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hu","family":"Yan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xian","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dihan","family":"Zhou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maohua","family":"Zhong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jingyi","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bali","family":"Zhao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xuxu","family":"Fan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jun","family":"Fan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiayi","family":"Shu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mengji","family":"Lu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xia","family":"Jin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2421-6749","authenticated-orcid":true,"given":"Ejuan","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huimin","family":"Yan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2022,1,31]]},"reference":[{"issue":"suppl 5","key":"pntd.0010149.ref001","doi-asserted-by":"crossref","first-page":"S488","DOI":"10.1093\/infdis\/jiw271","article-title":"Development of Vaccines for Chikungunya Fever","volume":"214","author":"JH Erasmus","year":"2016","journal-title":"J Infect Dis"},{"issue":"1","key":"pntd.0010149.ref002","doi-asserted-by":"crossref","first-page":"e00104","DOI":"10.1128\/CMR.00104-16","article-title":"Vaccine and Therapeutic Options To Control Chikungunya Virus.","volume":"31","author":"AM Powers","year":"2018","journal-title":"Clin Microbiol Rev"},{"issue":"10","key":"pntd.0010149.ref003","doi-asserted-by":"crossref","first-page":"e7603","DOI":"10.1371\/journal.pone.0007603","article-title":"Prospective study of Chikungunya virus acute infection in the Island of La Reunion during the 2005\u20132006 outbreak.","volume":"4","author":"F Staikowsky","year":"2009","journal-title":"PLoS One"},{"issue":"1","key":"pntd.0010149.ref004","doi-asserted-by":"crossref","first-page":"e2004","DOI":"10.1371\/journal.pntd.0002004","article-title":"Chikungunya fever: a clinical and virological investigation of outpatients on Reunion Island, South-West Indian Ocean.","volume":"7","author":"SD Thiberville","year":"2013","journal-title":"PLoS Negl Trop Dis"},{"issue":"13","key":"pntd.0010149.ref005","doi-asserted-by":"crossref","first-page":"1231","DOI":"10.1056\/NEJMra1406035","article-title":"Chikungunya virus and the global spread of a mosquito-borne disease","volume":"372","author":"SC Weaver","year":"2015","journal-title":"N Engl J Med"},{"issue":"3","key":"pntd.0010149.ref006","doi-asserted-by":"crossref","first-page":"e2137","DOI":"10.1371\/journal.pntd.0002137","article-title":"Chikungunya virus-associated long-term arthralgia: a 36-month prospective longitudinal study.","volume":"7","author":"C Schilte","year":"2013","journal-title":"PLoS Negl Trop Dis"},{"issue":"4","key":"pntd.0010149.ref007","doi-asserted-by":"crossref","first-page":"469","DOI":"10.1086\/590003","article-title":"Persistent arthralgia associated with chikungunya virus: a study of 88 adult patients on reunion island","volume":"47","author":"G Borgherini","year":"2008","journal-title":"Clin Infect Dis"},{"issue":"10","key":"pntd.0010149.ref008","doi-asserted-by":"crossref","first-page":"5914","DOI":"10.4049\/jimmunol.0900255","article-title":"Persistent chronic inflammation and infection by Chikungunya arthritogenic alphavirus in spite of a robust host immune response","volume":"184","author":"JJ Hoarau","year":"2010","journal-title":"J Immunol"},{"issue":"6","key":"pntd.0010149.ref009","doi-asserted-by":"crossref","first-page":"e527","DOI":"10.1371\/journal.pone.0000527","article-title":"Human muscle satellite cells as targets of Chikungunya virus infection.","volume":"2","author":"S Ozden","year":"2007","journal-title":"PLoS One"},{"issue":"3","key":"pntd.0010149.ref010","doi-asserted-by":"crossref","first-page":"894","DOI":"10.1172\/JCI40104","article-title":"Chikungunya disease in nonhuman primates involves long-term viral persistence in macrophages","volume":"120","author":"K Labadie","year":"2010","journal-title":"J Clin Invest"},{"issue":"7","key":"pntd.0010149.ref011","doi-asserted-by":"crossref","first-page":"e2343","DOI":"10.1371\/journal.pntd.0002343","article-title":"Chikungunya virus infection results in higher and persistent viral replication in aged rhesus macaques due to defects in anti-viral immunity","volume":"7","author":"I Messaoudi","year":"2013","journal-title":"PLoS Negl Trop Dis"},{"issue":"12","key":"pntd.0010149.ref012","doi-asserted-by":"crossref","first-page":"e3354","DOI":"10.1371\/journal.pntd.0003354","article-title":"Multiple immune factors are involved in controlling acute and chronic chikungunya virus infection.","volume":"8","author":"YS Poo","year":"2014","journal-title":"PLoS Negl Trop Dis"},{"issue":"8","key":"pntd.0010149.ref013","doi-asserted-by":"crossref","first-page":"e1007993","DOI":"10.1371\/journal.ppat.1007993","article-title":"Dermal and muscle fibroblasts and skeletal myofibers survive chikungunya virus infection and harbor persistent RNA","volume":"15","author":"AR Young","year":"2019","journal-title":"PLoS Pathog"},{"issue":"1","key":"pntd.0010149.ref014","doi-asserted-by":"crossref","first-page":"433","DOI":"10.1128\/JVI.02159-15","article-title":"gammadelta T Cells Play a Protective Role in Chikungunya Virus-Induced Disease","volume":"90","author":"KM Long","year":"2016","journal-title":"J Virol"},{"issue":"8","key":"pntd.0010149.ref015","doi-asserted-by":"crossref","first-page":"4047","DOI":"10.4049\/jimmunol.1201240","article-title":"Genetic ablation of arginase 1 in macrophages and neutrophils enhances clearance of an arthritogenic alphavirus","volume":"189","author":"KA Stoermer","year":"2012","journal-title":"J Immunol"},{"issue":"16","key":"pntd.0010149.ref016","doi-asserted-by":"crossref","first-page":"8021","DOI":"10.1128\/JVI.02603-09","article-title":"Chikungunya virus arthritis in adult wild-type mice","volume":"84","author":"J Gardner","year":"2010","journal-title":"J Virol"},{"issue":"1","key":"pntd.0010149.ref017","doi-asserted-by":"crossref","first-page":"259","DOI":"10.4049\/jimmunol.1202177","article-title":"A pathogenic role for CD4+ T cells during Chikungunya virus infection in mice","volume":"190","author":"TH Teo","year":"2013","journal-title":"J Immunol"},{"issue":"2","key":"pntd.0010149.ref018","doi-asserted-by":"crossref","first-page":"e29","DOI":"10.1371\/journal.ppat.0040029","article-title":"A mouse model for Chikungunya: young age and inefficient type-I interferon signaling are risk factors for severe disease.","volume":"4","author":"T Couderc","year":"2008","journal-title":"PLoS Pathog"},{"key":"pntd.0010149.ref019","article-title":"Development of Neutralization Assay Using an eGFP Chikungunya Virus.","author":"CL Deng","journal-title":"LID\u2014"},{"issue":"1","key":"pntd.0010149.ref020","doi-asserted-by":"crossref","first-page":"14641","DOI":"10.1038\/s41598-017-15269-w","article-title":"Evaluation of a range of mammalian and mosquito cell lines for use in Chikungunya virus research","volume":"7","author":"GC Roberts","year":"2017","journal-title":"Sci Rep"},{"issue":"10","key":"pntd.0010149.ref021","doi-asserted-by":"crossref","first-page":"e7468","DOI":"10.1371\/journal.pone.0007468","article-title":"Accurate strand-specific quantification of viral RNA","volume":"4","author":"NE Plaskon","year":"2009","journal-title":"PLoS One"},{"key":"pntd.0010149.ref022","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1016\/j.jviromet.2016.05.003","article-title":"High yield expression and purification of Chikungunya virus E2 recombinant protein and its evaluation for serodiagnosis","volume":"235","author":"A Verma","year":"2016","journal-title":"J Virol Methods"},{"issue":"13","key":"pntd.0010149.ref023","doi-asserted-by":"crossref","first-page":"7156","DOI":"10.1128\/JVI.02711-06","article-title":"Acute resolving woodchuck hepatitis virus (WHV) infection is associated with a strong cytotoxic T-lymphocyte response to a single WHV core peptide.","volume":"81","author":"I Frank","year":"2007","journal-title":"J Virol"},{"issue":"40","key":"pntd.0010149.ref024","doi-asserted-by":"crossref","first-page":"5128","DOI":"10.1016\/j.vaccine.2008.03.060","article-title":"Immunogenicity of novel consensus-based DNA vaccines against Chikungunya virus","volume":"26","author":"K Muthumani","year":"2008","journal-title":"Vaccine"},{"issue":"8","key":"pntd.0010149.ref025","doi-asserted-by":"crossref","first-page":"e0004960","DOI":"10.1371\/journal.pntd.0004960","article-title":"Antigenic Variation of East\/Central\/South African and Asian Chikungunya Virus Genotypes in Neutralization by Immune Sera.","volume":"10","author":"CL Chua","year":"2016","journal-title":"PLoS Negl Trop Dis."},{"key":"pntd.0010149.ref026","doi-asserted-by":"crossref","first-page":"345","DOI":"10.3389\/fcimb.2018.00345","article-title":"Cellular and Molecular Immune Response to Chikungunya Virus Infection.","volume":"8","author":"ISB Tanabe","year":"2018","journal-title":"Front Cell Infect Microbiol"},{"key":"pntd.0010149.ref027","first-page":"e65","article-title":"Minimum infectious dose for chikungunya virus in Aedes aegypti and Ae. albopictus mosquitoes.","volume":"41","author":"JP Ledermann","year":"2017","journal-title":"Rev Panam Salud Publica"},{"key":"pntd.0010149.ref028","doi-asserted-by":"crossref","first-page":"68","DOI":"10.1016\/j.jcv.2019.06.001","article-title":"Characterization of antibody response in patients with acute and chronic chikungunya virus disease.","volume":"117","author":"F Anfasa","year":"2019","journal-title":"J Clin Virol"},{"issue":"33","key":"pntd.0010149.ref029","doi-asserted-by":"crossref","first-page":"3353","DOI":"10.1016\/j.vaccine.2013.05.059","article-title":"Deciphering the protective role of adaptive immunity to CHIKV\/IRES a novel candidate vaccine against Chikungunya in the A129 mouse model","volume":"31","author":"H Chu","year":"2013","journal-title":"Vaccine"},{"issue":"1","key":"pntd.0010149.ref030","doi-asserted-by":"crossref","first-page":"115","DOI":"10.1093\/infdis\/jiq006","article-title":"The acute phase of Chikungunya virus infection in humans is associated with strong innate immunity and T CD8 cell activation","volume":"204","author":"N Wauquier","year":"2011","journal-title":"J Infect Dis"},{"issue":"9","key":"pntd.0010149.ref031","doi-asserted-by":"crossref","first-page":"1171","DOI":"10.1586\/1744666X.2014.942288","article-title":"Immune responses in neonates","volume":"10","author":"S Basha","year":"2014","journal-title":"Expert Rev Clin Immunol"},{"issue":"7","key":"pntd.0010149.ref032","doi-asserted-by":"crossref","first-page":"837","DOI":"10.2217\/fmb.09.59","article-title":"A structural and functional perspective of alphavirus replication and assembly.","volume":"4","author":"J Jose","year":"2009","journal-title":"Future Microbiol"},{"issue":"1","key":"pntd.0010149.ref033","doi-asserted-by":"crossref","first-page":"132","DOI":"10.4269\/ajtmh.2006.74.132","article-title":"Quantitative analysis of dengue-2 virus RNA during the extrinsic incubation period in individual Aedes aegypti","volume":"74","author":"J Richardson","year":"2006","journal-title":"Am J Trop Med Hyg"},{"issue":"1","key":"pntd.0010149.ref034","doi-asserted-by":"crossref","first-page":"250","DOI":"10.1186\/1743-422X-7-250","article-title":"Use of a highly sensitive strand-specific quantitative PCR to identify abortive replication in the mouse model of respiratory syncytial virus disease.","volume":"7","author":"R Bannister","year":"2010","journal-title":"Virol J."},{"issue":"3","key":"pntd.0010149.ref035","doi-asserted-by":"crossref","first-page":"1874","DOI":"10.1128\/jvi.68.3.1874-1885.1994","article-title":"Regulation of Sindbis virus RNA replication: uncleaved P123 and nsP4 function in minus-strand RNA synthesis, whereas cleaved products from P123 are required for efficient plus-strand RNA synthesis","volume":"68","author":"Y Shirako","year":"1994","journal-title":"J Virol"}],"container-title":["PLOS Neglected Tropical Diseases"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pntd.0010149","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,1,31]],"date-time":"2022-01-31T13:22:30Z","timestamp":1643635350000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pntd.0010149"}},"subtitle":[],"editor":[{"given":"Ran","family":"Wang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2022,1,31]]},"references-count":35,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2022,1,31]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pntd.0010149","relation":{},"ISSN":["1935-2735"],"issn-type":[{"value":"1935-2735","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,1,31]]}}}