Unknown,Transcriptomics,Genomics,Proteomics

Dataset Information

RNA-seq of SARS-CoV-2-infected human primary hepatocyte-derived spheroids upon interferon a2 and baricitinib treatment

ABSTRACT: Biological replicates of liver spheroids derived from primary hepatocytes were treated with IFNa2 and/or baricitinib for 24 h and subsequently infected with Sars-CoV-2. The cells were harvested 48 h time after infection. Total RNA was extracted and sequenced with a strand-specific paired end RNA-seq protocol.

INSTRUMENT(S): NextSeq 500

ORGANISM(S): Homo sapiens

SUBMITTER: Claudia Kutter

PROVIDER: E-MTAB-9711 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Publications

JAK inhibition reduces SARS-CoV-2 liver infectivity and modulates inflammatory responses to reduce morbidity and mortality.

Stebbing Justin J Sánchez Nievas Ginés G Falcone Marco M Youhanna Sonia S Richardson Peter P Ottaviani Silvia S Shen Joanne X JX Sommerauer Christian C Tiseo Giusy G Ghiadoni Lorenzo L Virdis Agostino A Monzani Fabio F Rizos Luis Romero LR Forfori Francesco F Avendaño Céspedes Almudena A De Marco Salvatore S Carrozzi Laura L Lena Fabio F Sánchez-Jurado Pedro Manuel PM Lacerenza Leonardo Gianluca LG Cesira Nencioni N Caldevilla Bernardo David D Perrella Antonio A Niccoli Laura L Méndez Lourdes Sáez LS Matarrese Daniela D Goletti Delia D Tan Yee-Joo YJ Monteil Vanessa V Dranitsaris George G Cantini Fabrizio F Farcomeni Alessio A Dutta Shuchismita S Burley Stephen K SK Zhang Haibo H Pistello Mauro M Li William W Romero Marta Mas MM Andrés Pretel Fernando F Simón-Talero Rafaela Sánchez RS García-Molina Rafael R Kutter Claudia C Felce James H JH Nizami Zehra F ZF Miklosi Andras G AG Penninger Josef M JM Menichetti Francesco F Mirazimi Ali A Abizanda Pedro P Lauschke Volker M VM

Science advances 20210101 1

Using AI, we identified baricitinib as having antiviral and anticytokine efficacy. We now show a 71% (95% CI 0.15 to 0.58) mortality benefit in 83 patients with moderate-severe SARS-CoV-2 pneumonia with few drug-induced adverse events, including a large elderly cohort (median age, 81 years). An additional 48 cases with mild-moderate pneumonia recovered uneventfully. Using organotypic 3D cultures of primary human liver cells, we demonstrate that interferon-α2 increases ACE2 expression and SARS-Co ...[more]

PMID: 33187978

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Project description:It is well-known that isolation and cultivation of primary hepatocytes causes major gene expression alterations. In the present genome-wide, time resolved study of cultivated human and mouse hepatocytes, we made the observation that expression changes in culture strongly resemble alterations in liver diseases. Hepatocytes of both species were cultivated in collagen sandwich and in monolayer conditions. Genome-wide data were also obtained from human NAFLD, cirrhosis, HCC, and hepatitis B virus infected tissue as well as mouse livers after partial hepatectomy, CCl4 intoxication, obesity, HCC and LPS. A strong similarity between cultivation and disease induced expression alterations was observed. For example, expression changes in hepatocytes induced by one day cultivation and one day CCl4 exposure in vivo correlated with R=0.615 (P<0.001). Interspecies comparison identified predominantly similar responses in human and mouse hepatocytes but also a minority of genes that responded differently. Unsupervised clustering of altered genes identified three main clusters: (1) downregulated genes corresponding to mature liver functions, (2) upregulation of an inflammation/RNA-processing cluster, (3) upregulated migration/cell-cycle associated genes. Gene regulatory network analysis highlights overrepresented and deregulated HNF4 and CAR (cluster 1), KrÃ¼ppel-like factors MafF and ELK1 (cluster 2) as well as ETF (cluster 3) among the interspecies conserved key regulators of expression changes. Interventions ameliorating but by far not abrogating cultivation-induced responses include removal of non-parenchymal cells, generation of the hepatocytesâ own matrix in spheroids, supplementation with bile salts and siRNA mediated suppression of key transcription factors. In conclusion, the study shows that gene regulatory network alterations of cultivated hepatocytes resemble those of inflammatory liver diseases and should therefore be considered and exploited as disease models.

Dataset Information

RNA-seq of SARS-CoV-2-infected human primary hepatocyte-derived spheroids upon interferon a2 and baricitinib treatment

Publications

JAK inhibition reduces SARS-CoV-2 liver infectivity and modulates inflammatory responses to reduce morbidity and mortality.

Similar Datasets

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