{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T06:10:43Z","timestamp":1790230243246,"version":"4.1.0"},"reference-count":61,"publisher":"American Society for Microbiology","issue":"7","license":[{"start":{"date-parts":[[2024,7,23]],"date-time":"2024-07-23T00:00:00Z","timestamp":1721692800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/doi.org\/10.1128\/ASMCopyrightv2"},{"start":{"date-parts":[[2024,7,23]],"date-time":"2024-07-23T00:00:00Z","timestamp":1721692800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.asm.org\/non-commercial-tdm-license"}],"funder":[{"DOI":"10.13039\/100008519","name":"University of Arkansas for Medical Sciences","doi-asserted-by":"crossref","id":[{"id":"10.13039\/100008519","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["journals.asm.org"],"crossmark-restriction":true},"short-container-title":["J Virol"],"published-print":{"date-parts":[[2024,7,23]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n          <jats:sec>\n            <jats:title\/>\n            <jats:p>\n              Coronavirus disease 2019 (COVID-19) has claimed millions of lives since the emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and lung disease appears the primary cause of death in COVID-19 patients. However, the underlying mechanisms of COVID-19 pathogenesis remain elusive, and there is no existing model where human disease can be faithfully recapitulated and conditions for the infection process can be experimentally controlled. Herein we report the establishment of an\n              <jats:italic>ex vivo<\/jats:italic>\n              human precision-cut lung slice (hPCLS) platform for studying SARS-CoV-2 pathogenicity and innate immune responses, and for evaluating the efficacy of antiviral drugs against SARS-CoV-2. We show that while SARS-CoV-2 continued to replicate during the course of infection of hPCLS, infectious virus production peaked within 2 days, and rapidly declined thereafter. Although most proinflammatory cytokines examined were induced by SARS-CoV-2 infection, the degree of induction and types of cytokines varied significantly among hPCLS from individual donors. Two cytokines in particular, IP-10 and IL-8, were highly and consistently induced, suggesting a role in the pathogenesis of COVID-19. Histopathological examination revealed focal cytopathic effects late in the infection. Transcriptomic and proteomic analyses identified molecular signatures and cellular pathways that are largely consistent with the progression of COVID-19 in patients. Furthermore, we show that homoharringtonine, a natural plant alkaloid derived from\n              <jats:italic>Cephalotoxus fortunei<\/jats:italic>\n              , not only inhibited virus replication but also production of pro-inflammatory cytokines, and thus ameliorated the histopathological changes caused by SARS-CoV-2 infection, demonstrating the usefulness of the hPCLS platform for evaluating antiviral drugs.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>IMPORTANCE<\/jats:title>\n            <jats:p>\n              Here, established an\n              <jats:italic>ex vivo<\/jats:italic>\n              human precision-cut lung slice platform for assessing severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, viral replication kinetics, innate immune response, disease progression, and antiviral drugs. Using this platform, we identified early induction of specific cytokines, especially IP-10 and IL-8, as potential predictors for severe coronavirus disease 2019 (COVID-19), and uncovered a hitherto unrecognized phenomenon that while infectious virus disappears at late times of infection, viral RNA persists and lung histopathology commences. This finding may have important clinical implications for both acute and post-acute sequelae of COVID-19. This platform recapitulates some of the characteristics of lung disease observed in severe COVID-19 patients and is therefore a useful platform for understanding mechanisms of SARS-CoV-2 pathogenesis and for evaluating the efficacy of antiviral drugs.\n            <\/jats:p>\n          <\/jats:sec>","DOI":"10.1128\/jvi.00794-24","type":"journal-article","created":{"date-parts":[[2024,6,28]],"date-time":"2024-06-28T13:13:21Z","timestamp":1719580401000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":12,"title":["An\n            <i>ex vivo<\/i>\n            human precision-cut lung slice platform provides insight into SARS-CoV-2 pathogenesis and antiviral drug efficacy"],"prefix":"10.1128","volume":"98","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5434-4744","authenticated-orcid":true,"given":"Roger D.","family":"Pechous","sequence":"first","affiliation":[{"name":"Department of Microbiology and Immunology, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Priyangi A.","family":"Malaviarachchi","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Srijon K.","family":"Banerjee","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephanie D.","family":"Byrum","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA"},{"name":"Arkansas Children\u2019s Research Institute, Little Rock, Arkansas, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Duah H.","family":"Alkam","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alireza","family":"Ghaffarieh","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA"},{"name":"Department of Pathology, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard C.","family":"Kurten","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA"},{"name":"Lung Cell Biology Laboratory, Arkansas Children\u2019s Research Institute, Little Rock, Arkansas, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1919-9051","authenticated-orcid":true,"given":"Joshua L.","family":"Kennedy","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA"},{"name":"Lung Cell Biology Laboratory, Arkansas Children\u2019s Research Institute, Little Rock, Arkansas, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0305-101X","authenticated-orcid":true,"given":"Xuming","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"235","reference":[{"key":"e_1_3_4_2_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(20)31305-2"},{"key":"e_1_3_4_3_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(20)30183-5"},{"key":"e_1_3_4_4_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2001017"},{"key":"e_1_3_4_5_2","first-page":"114","article-title":"Lost in translation: animal models and clinical trials in cancer treatment","volume":"6","author":"Mak IW","year":"2014","unstructured":"Mak IW, Evaniew N, Ghert M. 2014. 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