SARS-CoV-2 infection of human pluripotent stem cell-derived liver organoids reveals potential mechanisms of liver pathology (scRNA-Seq)
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE210059 | GEO | 2022/10/04
REPOSITORIES: GEO
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Project description:Symptoms of liver damage are observed in nearly half of patients that succumb to severe SARS-CoV-2 infection. Here we use human induced pluripotent stem cell-derived liver organoids (HLOs) to recapitulate and characterize liver pathology following virus exposure. Utilizing single-cell sequencing technology, we identified robust transcriptomic changes that occur in SARS-CoV-2 infected liver cells as well as uninfected bystander cells. Our results show a significant induction of many inflammatory pathways, including IFN-α, INF-γ and IL-6 signaling. Our results further identify IL-6 signaling as a potential mechanism for liver-mediated activation of circulating macrophages.
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Project description:iPSCs were differentiated to human liver organoids as previously described. Human liver organoids were dispersed into single-cell suspension with trypsin (0.25%) and transferred to both channels in an dual-channel organ on chip system and cultured in hepatocyte maturation media. Media flow was regulated to 30 µL/hr for both channels. After 7 days of culture, liver chips were treated with vehicle control, or DILI-related compounds APAP, FIAU, tenofovir, or a tenofovir-inarigivir combination. scRNA sequencing was performed on intact HLOs and liver chips treated with each condition to compare HLOs pre- and post-chip and provide mechanistic DILI insight of treatments. Each sample generated between 440 and 860 million barcoded reads corresponding to an estimated 4,600 to 25,000 cells per sample
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Project description:Severe acute respiratory syndrome coronavirus (SARS-CoV) causes lethal disease in humans, with viral E protein promoting the exacerbated inflammatory response. By deep sequencing RNAs from the lungs of infected mice, we have addressed the relevance of small, non-coding RNAs in SARS-CoV pathology. Host microRNAs (miRNAs) expressed during infection by a virulent virus encoding the E protein were significantly enriched for cytokine-mediated inflammatory pathways when compared with attenuated SARS-CoV-∆E, suggesting contribution of miRNAs to E protein-induced inflammation. The discovery of three 18-22 nt small viral RNAs (svRNAs) derived from the nsp3 and N genomic regions of SARS-CoV in mouse lung and cell cultures is also described. Depletion of these svRNAs significantly reduced viral titers and genomic RNA levels, indicating their positive contribution to virus growth. Remarkably, svRNA-N antagomirs significantly reduced in vivo lung pathology and pro-inflammatory cytokine expression, indicating that svRNAs contribute to SARS-CoV pathogenesis and highlighting the potential of these antagomirs as antivirals.
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