{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,4]],"date-time":"2026-06-04T14:18:45Z","timestamp":1780582725145,"version":"3.54.1"},"reference-count":24,"publisher":"Oxford University Press (OUP)","issue":"11","license":[{"start":{"date-parts":[[2022,4,19]],"date-time":"2022-04-19T00:00:00Z","timestamp":1650326400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2022,11,30]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:sec>\n                  <jats:title>Background<\/jats:title>\n                  <jats:p>The multiple mutations comprising the epsilon variant demonstrate the independent convergent evolution of severe acute respiratory syndrome coronavirus (SARS-CoV-2), with its spike protein mutation L452R present in the delta (L452R), kappa (L452R), and lambda (L452Q) variants.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>Coronavirus disease 2019 (COVID-19) variants were detected in 1017 patients using whole-genome sequencing and were assessed for outcome and severity. The mechanistic effects of the epsilon versus non-epsilon variants were investigated using a multiomic approach including cellular response assays and paired cell and host transcriptomic and proteomic profiling.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>We found that patients carrying the epsilon variant had increased mortality risk but not increased hospitalizations (P &amp;lt; .02). Cells infected with live epsilon compared with non-epsilon virus displayed increased sensitivity to neutralization antibodies in all patients but a slightly protective response in vaccinated individuals (P &amp;lt; .001). That the epsilon SARS-CoV-2 variant is more infectious but less virulent is supported mechanistically in the down-regulation of viral processing pathways seen by multiomic analyses. Importantly, this paired transcriptomics and proteomic profiling of host cellular response to live virus revealed an altered leukocyte response and metabolic messenger RNA processing with the epsilon variant. To ascertain host response to SARS-CoV-2 infection, primary COVID-19\u2013positive nasopharyngeal samples were transcriptomically profiled and revealed a differential innate immune response (P &amp;lt; .001) and an adjusted T-cell response in patients carrying the epsilon variant (P &amp;lt; .002). In fact, patients infected with SARS-CoV-2 and those vaccinated with the BNT162b2 vaccine have comparable CD4+\/CD8+ T-cell immune responses to the epsilon variant (P &amp;lt; .05).<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusions<\/jats:title>\n                  <jats:p>While the epsilon variant is more infectious, by altering viral processing, we showed that patients with COVID-19 have adapted their innate immune response to this fitter variant. A protective T-cell response molecular signature is generated by this more transmissible variant in both vaccinated and unvaccinated patients.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1093\/cid\/ciac295","type":"journal-article","created":{"date-parts":[[2022,4,15]],"date-time":"2022-04-15T04:00:04Z","timestamp":1649995204000},"page":"1940-1949","source":"Crossref","is-referenced-by-count":4,"title":["US Severe Acute Respiratory Syndrome Coronavirus 2 Epsilon Variant: Highly Transmissible but With an Adjusted Muted Host T-Cell Response"],"prefix":"10.1093","volume":"75","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7263-350X","authenticated-orcid":false,"given":"Jasmine T","family":"Plummer","sequence":"first","affiliation":[{"name":"Center for Bioinformatics and Functional Genomics, Cedars-Sinai Medical Center , Los Angeles, California , USA"},{"name":"Applied Genomics, Computation & Translational Core, Cedars-Sinai Cancer, Cedars-Sinai Medical Center , Los Angeles, California , USA"},{"name":"Department of Biomedical Sciences, Cedars-Sinai Medical Center , Los Angeles, California , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Deisy","family":"Contreras","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences, Cedars-Sinai Medical Center , Los Angeles, California , USA"},{"name":"Clinical Microbiology Laboratory, Cedars-Sinai Medical Center , Los Angeles, California , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenjuan","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Pathology & Laboratory Medicine, Cedars-Sinai Medical Center , Los Angeles, California , USA"},{"name":"Molecular Pathology Laboratory, Cedars-Sinai Medical Center , Los Angeles, California , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aleksandra","family":"Binek","sequence":"additional","affiliation":[{"name":"Smidt Heart Institute, Cedars-Sinai Medical Center , Los Angeles, California , USA"},{"name":"Department of Medicine, Cedars-Sinai Medical Center , Los Angeles, California , USA"},{"name":"Advanced Clinical Biosystems Institute, Cedars-Sinai Medical Center , Los Angeles, California , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruan","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Medicine, Cedars-Sinai Medical Center , Los Angeles, California , USA"},{"name":"HLA and Transplant Immunology Laboratory, Cedars-Sinai Medical Center , Los Angeles, California , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Felipe","family":"Dezem","sequence":"additional","affiliation":[{"name":"Center for Bioinformatics and Functional Genomics, Cedars-Sinai Medical Center , Los Angeles, California , USA"},{"name":"Department of Biomedical Sciences, Cedars-Sinai Medical Center , Los Angeles, California , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephanie S","family":"Chen","sequence":"additional","affiliation":[{"name":"Center for Bioinformatics and Functional Genomics, Cedars-Sinai Medical Center , Los Angeles, California , USA"},{"name":"Applied Genomics, Computation & Translational Core, Cedars-Sinai Cancer, Cedars-Sinai Medical Center , Los Angeles, California , USA"},{"name":"Department of Biomedical Sciences, Cedars-Sinai Medical Center , Los Angeles, California , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brian D","family":"Davis","sequence":"additional","affiliation":[{"name":"Center for Bioinformatics and Functional Genomics, Cedars-Sinai Medical Center , Los Angeles, California , USA"},{"name":"Applied Genomics, Computation & Translational Core, Cedars-Sinai Cancer, Cedars-Sinai Medical Center , Los Angeles, California , USA"},{"name":"Department of Biomedical Sciences, Cedars-Sinai Medical Center , Los Angeles, California , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jorge","family":"Sincuir Martinez","sequence":"additional","affiliation":[{"name":"Department of Pathology & Laboratory Medicine, Cedars-Sinai Medical Center , Los Angeles, California , USA"},{"name":"Molecular Pathology Laboratory, Cedars-Sinai Medical Center , Los Angeles, California , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aleksandr","family":"Stotland","sequence":"additional","affiliation":[{"name":"Smidt Heart Institute, Cedars-Sinai Medical Center , Los Angeles, California , USA"},{"name":"Department of Medicine, Cedars-Sinai Medical Center , Los Angeles, California , USA"},{"name":"Advanced Clinical Biosystems Institute, Cedars-Sinai Medical Center , Los Angeles, California , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Simion","family":"Kreimer","sequence":"additional","affiliation":[{"name":"Smidt Heart Institute, Cedars-Sinai Medical Center , Los Angeles, California , USA"},{"name":"Department of Medicine, Cedars-Sinai Medical Center , Los Angeles, California , USA"},{"name":"Advanced Clinical Biosystems Institute, Cedars-Sinai Medical Center , Los Angeles, California , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elias","family":"Makhoul","sequence":"additional","affiliation":[{"name":"Department of Pathology & Laboratory Medicine, Cedars-Sinai Medical Center , Los Angeles, California , USA"},{"name":"Molecular Pathology Laboratory, Cedars-Sinai Medical Center , Los Angeles, California , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Saleh","family":"Heneidi","sequence":"additional","affiliation":[{"name":"Department of Pathology & Laboratory Medicine, Cedars-Sinai Medical Center , Los Angeles, California , USA"},{"name":"Molecular Pathology Laboratory, Cedars-Sinai Medical Center , Los Angeles, California , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Celeste","family":"Eno","sequence":"additional","affiliation":[{"name":"Department of Pathology & Laboratory Medicine, Cedars-Sinai Medical Center , Los Angeles, California , USA"},{"name":"Molecular Pathology Laboratory, Cedars-Sinai Medical Center , Los Angeles, California , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bongha","family":"Shin","sequence":"additional","affiliation":[{"name":"Department of Medicine, Cedars-Sinai Medical Center , Los Angeles, California , USA"},{"name":"HLA and Transplant Immunology Laboratory, Cedars-Sinai Medical Center , Los Angeles, California , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anders H","family":"Berg","sequence":"additional","affiliation":[{"name":"Department of Pathology & Laboratory Medicine, Cedars-Sinai Medical Center , Los Angeles, California , USA"},{"name":"Department of Medicine, Cedars-Sinai Medical Center , Los Angeles, California , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Susan","family":"Cheng","sequence":"additional","affiliation":[{"name":"Smidt Heart Institute, Cedars-Sinai Medical Center , Los Angeles, California , USA"},{"name":"Department of Medicine, Cedars-Sinai Medical Center , Los Angeles, California , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"name":"CORALE Study Group","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stanley C","family":"Jordan","sequence":"additional","affiliation":[{"name":"Department of Medicine, Cedars-Sinai Medical Center , Los Angeles, California , USA"},{"name":"HLA and Transplant Immunology Laboratory, Cedars-Sinai Medical Center , Los Angeles, California , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eric","family":"Vail","sequence":"additional","affiliation":[{"name":"Department of Pathology & Laboratory Medicine, Cedars-Sinai Medical Center , Los Angeles, California , USA"},{"name":"Molecular Pathology Laboratory, Cedars-Sinai Medical Center , Los Angeles, California , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jennifer E","family":"Van Eyk","sequence":"additional","affiliation":[{"name":"Smidt Heart Institute, Cedars-Sinai Medical Center , Los Angeles, California , USA"},{"name":"Department of Medicine, Cedars-Sinai Medical Center , Los Angeles, California , USA"},{"name":"Advanced Clinical Biosystems Institute, Cedars-Sinai Medical Center , Los Angeles, California , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Margie A","family":"Morgan","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences, Cedars-Sinai Medical Center , Los Angeles, California , USA"},{"name":"Clinical Microbiology Laboratory, Cedars-Sinai Medical Center , Los Angeles, California , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2022,4,19]]},"reference":[{"key":"2022113017003234200_ciac295-B1","doi-asserted-by":"crossref","first-page":"2002106","DOI":"10.2807\/1560-7917.ES.2020.26.1.2002106","article-title":"Early transmissibility assessment of the N501Y mutant strains of SARS-CoV-2 in the United Kingdom","volume":"26","author":"Leung","year":"2021","journal-title":"Euro Surveill"},{"key":"2022113017003234200_ciac295-B2","doi-asserted-by":"crossref","first-page":"553","DOI":"10.1038\/s41586-021-03594-0","article-title":"Neutralizing antibody vaccine for pandemic and pre-emergent coronaviruses","volume":"594","author":"Saunders","year":"2021","journal-title":"Nature"},{"key":"2022113017003234200_ciac295-B3","doi-asserted-by":"crossref","first-page":"1109","DOI":"10.1016\/j.cmi.2021.05.022","article-title":"Novel SARS-CoV-2 variants: the pandemics within the pandemic","volume":"27","author":"Boehm","year":"2021","journal-title":"Clin Microbiol Infect"},{"key":"2022113017003234200_ciac295-B4","doi-asserted-by":"crossref","first-page":"2372","DOI":"10.1016\/j.cell.2021.03.013","article-title":"Multiple SARS-CoV-2 variants escape neutralization by vaccine-induced humoral immunity","volume":"184(9)","author":"Garcia-Beltran","year":"2021","journal-title":"Cell"},{"key":"2022113017003234200_ciac295-B5","doi-asserted-by":"crossref","first-page":"e14062","DOI":"10.15252\/emmm.202114062","article-title":"SARS-CoV-2 worldwide replication drives rapid rise and selection of mutations across the viral genome: a time-course study\u2014potential challenge for vaccines and therapies","volume":"13","author":"Weber","year":"2021","journal-title":"EMBO Mol Med"},{"key":"2022113017003234200_ciac295-B6","doi-asserted-by":"crossref","first-page":"276","DOI":"10.1038\/s41586-021-03777-9","article-title":"Reduced sensitivity of SARS-CoV-2 variant delta to antibody neutralization","volume":"596","author":"Planas","year":"2021","journal-title":"Nature"},{"key":"2022113017003234200_ciac295-B7","doi-asserted-by":"crossref","first-page":"1324","DOI":"10.1001\/jama.2021.1612","article-title":"Emergence of a novel SARS-CoV-2 variant in Southern California","volume":"325","author":"Zhang","year":"2021","journal-title":"JAMA"},{"key":"2022113017003234200_ciac295-B8","doi-asserted-by":"publisher","DOI":"10.1101\/2021.03.07.21252647","article-title":"Transmission, infectivity, and antibody neutralization of an emerging SARS-CoV-2 variant in California carrying a L452R spike protein mutation","author":"Deng","journal-title":"medRxiv"},{"key":"2022113017003234200_ciac295-B9","author":"Centers for Disease Control and Prevention. US COVID-19 cases caused by variants"},{"key":"2022113017003234200_ciac295-B10","doi-asserted-by":"crossref","first-page":"110218","DOI":"10.1016\/j.celrep.2021.110218","article-title":"The SARS-CoV-2 lambda variant exhibits higher infectivity and immune resistance","volume":"38","author":"Kimura","year":"2022","journal-title":"Cell Rep"},{"key":"2022113017003234200_ciac295-B11","doi-asserted-by":"crossref","DOI":"10.1128\/JCM.00921-21","article-title":"Acquisition of the L452R mutation in the ACE2-binding interface of spike protein triggers recent massive expansion of SARS-CoV-2 variants","author":"Tchesnokova","year":"2021","journal-title":"J Clin Microbiol"},{"key":"2022113017003234200_ciac295-B12","doi-asserted-by":"crossref","first-page":"648","DOI":"10.1126\/science.abi7994","article-title":"SARS-CoV-2 immune evasion by the B.1.427\/B.1.429 variant of concern","volume":"373","author":"McCallum","year":"2021","journal-title":"Science"},{"key":"2022113017003234200_ciac295-B13","doi-asserted-by":"crossref","first-page":"3426","DOI":"10.1016\/j.cell.2021.04.025","article-title":"Transmission, infectivity, and neutralization of a spike L452R SARS-CoV-2 variant","volume":"184","author":"Deng","year":"2021","journal-title":"Cell"},{"key":"2022113017003234200_ciac295-B14","doi-asserted-by":"crossref","first-page":"1124","DOI":"10.1016\/j.chom.2021.06.006","article-title":"SARS-CoV-2 spike L452R variant evades cellular immunity and increases infectivity","volume":"29","author":"Motozono","year":"2021","journal-title":"Cell Host Microbe"},{"key":"2022113017003234200_ciac295-B15","doi-asserted-by":"crossref","first-page":"ofab143","DOI":"10.1093\/ofid\/ofab143","article-title":"CD8+ T cell responses in COVID-19 convalescent individuals target conserved epitopes from multiple prominent SARS-CoV-2 circulating variants","volume":"8","author":"Redd","year":"2021","journal-title":"Open Forum Infect Dis"},{"key":"2022113017003234200_ciac295-B16","doi-asserted-by":"crossref","first-page":"348","DOI":"10.1007\/s12250-020-00241-2","article-title":"Isolation and growth characteristics of SARS-CoV-2 in Vero cell","volume":"35","author":"Yao","year":"2020","journal-title":"Virol Sin"},{"key":"2022113017003234200_ciac295-B17","doi-asserted-by":"crossref","first-page":"457","DOI":"10.1038\/s41586-020-2550-z","article-title":"SARS-CoV-2-specific T cell immunity in cases of COVID-19 and SARS, and uninfected controls","volume":"584","author":"Le Bert","year":"2020","journal-title":"Nature"},{"key":"2022113017003234200_ciac295-B18","doi-asserted-by":"crossref","first-page":"270","DOI":"10.1038\/s41586-020-2598-9","article-title":"SARS-CoV-2-reactive T cells in healthy donors and patients with COVID-19","volume":"587","author":"Braun","year":"2020","journal-title":"Nature"},{"key":"2022113017003234200_ciac295-B19","doi-asserted-by":"crossref","first-page":"89","DOI":"10.1126\/science.abd3871","article-title":"Selective and cross-reactive SARS-CoV-2 T cell epitopes in unexposed humans","volume":"370","author":"Mateus","year":"2020","journal-title":"Science"},{"key":"2022113017003234200_ciac295-B20","doi-asserted-by":"crossref","first-page":"1336","DOI":"10.1038\/s41590-020-0782-6","article-title":"Broad and strong memory CD4+ and CD8+ T cells induced by SARS-CoV-2 in UK convalescent individuals following COVID-19","volume":"21","author":"Peng","year":"2020","journal-title":"Nat Immunol"},{"key":"2022113017003234200_ciac295-B21","doi-asserted-by":"crossref","first-page":"100355","DOI":"10.1016\/j.xcrm.2021.100355","article-title":"Impact of SARS-CoV-2 variants on the total CD4+ and CD8+ T cell reactivity in infected or vaccinated individuals","volume":"2","author":"Tarke","year":"2021","journal-title":"Cell Rep Med"},{"key":"2022113017003234200_ciac295-B22","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1038\/s41574-020-00435-4","article-title":"COVID-19 and diabetes mellitus: from pathophysiology to clinical management","volume":"17","author":"Lim","year":"2021","journal-title":"Nat Rev Endocrinol"},{"key":"2022113017003234200_ciac295-B23","doi-asserted-by":"crossref","first-page":"D442","DOI":"10.1093\/nar\/gky1106","article-title":"The PRIDE database and related tools and resources in 2019: improving support for quantification data","volume":"47","author":"Perez-Riverol","year":"2019","journal-title":"Nucleic Acids Res"},{"key":"2022113017003234200_ciac295-B24","first-page":"D1145","article-title":"The ProteomeXchange consortium in 2020: enabling \u2018big data\u2019 approaches in proteomics","volume":"48","author":"Deutsch","year":"2020","journal-title":"Nucleic Acids Res"}],"container-title":["Clinical Infectious Diseases"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/cid\/advance-article-pdf\/doi\/10.1093\/cid\/ciac295\/43983992\/ciac295.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/cid\/article-pdf\/75\/11\/1940\/47466349\/ciac295.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/cid\/article-pdf\/75\/11\/1940\/47466349\/ciac295.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,11,30]],"date-time":"2022-11-30T17:29:17Z","timestamp":1669829357000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/cid\/article\/75\/11\/1940\/6570676"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,4,19]]},"references-count":24,"journal-issue":{"issue":"11","published-online":{"date-parts":[[2022,4,19]]},"published-print":{"date-parts":[[2022,11,30]]}},"URL":"https:\/\/doi.org\/10.1093\/cid\/ciac295","relation":{},"ISSN":["1058-4838","1537-6591"],"issn-type":[{"value":"1058-4838","type":"print"},{"value":"1537-6591","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2022,12,1]]},"published":{"date-parts":[[2022,4,19]]}}}