دورية أكاديمية
أعرض في EDS

An ex vivo human precision-cut lung slice platform provides insight into SARS-CoV-2 pathogenesis and antiviral drug efficacy.

التفاصيل البيبلوغرافية
العنوان: An ex vivo human precision-cut lung slice platform provides insight into SARS-CoV-2 pathogenesis and antiviral drug efficacy.
المؤلفون: Pechous RD; Department of Microbiology and Immunology, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA., Malaviarachchi PA; Department of Microbiology and Immunology, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA., Banerjee SK; Department of Microbiology and Immunology, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA., Byrum SD; Department of Biochemistry and Molecular Biology, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA.; Arkansas Children's Research Institute, Little Rock, Arkansas, USA., Alkam DH; Department of Biochemistry and Molecular Biology, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA., Ghaffarieh A; Department of Ophthalmology, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA.; Department of Pathology, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA., Kurten RC; Department of Pediatrics, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA.; Lung Cell Biology Laboratory, Arkansas Children's Research Institute, Little Rock, Arkansas, USA., Kennedy JL; Department of Pediatrics, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA.; Lung Cell Biology Laboratory, Arkansas Children's Research Institute, Little Rock, Arkansas, USA., Zhang X; Department of Microbiology and Immunology, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA.
المصدر: Journal of virology [J Virol] 2024 Jul 23; Vol. 98 (7), pp. e0079424. Date of Electronic Publication: 2024 Jun 28.
نوع المنشور: Journal Article
اللغة: English
بيانات الدورية: Publisher: American Society For Microbiology Country of Publication: United States NLM ID: 0113724 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1098-5514 (Electronic) Linking ISSN: 0022538X NLM ISO Abbreviation: J Virol Subsets: MEDLINE
أسماء مطبوعة: Publication: Washington Dc : American Society For Microbiology
Original Publication: Baltimore, American Society for Microbiology.
مواضيع طبية MeSH: Lung*/virology , Lung*/pathology , Lung*/drug effects , SARS-CoV-2*/drug effects , SARS-CoV-2*/physiology , Antiviral Agents*/pharmacology , COVID-19*/virology , COVID-19*/pathology , Cytokines*/metabolism , Virus Replication*/drug effects, Humans ; Immunity, Innate ; COVID-19 Drug Treatment
مستخلص: 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 ex vivo 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 Cephalotoxus fortunei , 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.
Importance: Here, established an ex vivo 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.
Competing Interests: The authors declare no conflict of interest.
التعليقات: Update of: bioRxiv. 2023 Apr 19:2023.04.18.537373. doi: 10.1101/2023.04.18.537373. (PMID: 37131640)
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معلومات مُعتمدة: P20 GM121293 United States GM NIGMS NIH HHS; R24 GM137786 United States GM NIGMS NIH HHS; University of Arkansas for Medical Sciences (UAMS)
فهرسة مساهمة: Keywords: COVID-19; SARS-CoV-2; antiviral; drug testing; hPCLS; pathogenesis
المشرفين على المادة: 0 (Antiviral Agents)
0 (Cytokines)
تواريخ الأحداث: Date Created: 20240628 Date Completed: 20240723 Latest Revision: 20240725
رمز التحديث: 20240726
مُعرف محوري في PubMed: PMC11265413
DOI: 10.1128/jvi.00794-24
PMID: 38940558
قاعدة البيانات: MEDLINE
الوصف
تدمد:1098-5514
DOI:10.1128/jvi.00794-24