An ex vivo human precision-cut lung slice platform provides insight into SARS-CoV-2 pathogenesis and antiviral drug efficacy
COVID-19 has claimed millions of lives since the emergence of SARS-CoV-2, and lung disease appears the primary cause of the deaths in COVID-19 patients.  However, the underlying mechanisms of COVID-19 pathogenesis remain elusive and there is no existing model where the 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 response, 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, reflecting the heterogeneity of human populations.  In particular, two cytokines (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 homoherringtonine, a natural plant alkaloid derived from Cephalotoxus fortunei, not only inhibited virus replication but also production of pro-inflammatory cytokines, and ameliorated the histopathological changes of the lungs caused by SARS-CoV-2 infection, demonstrating the usefulness of the hPCLS platform for evaluating antiviral drugs. Overall design: Applied RNAseq to compare the transcriptomic profile of ex vivo human precision-cut lung slices (hPCLS) following infection from 24hr to 96hr with SARS-CoV-2, and compared them with those from uninfected hPCLS.