Transcriptomic profiling of SARS-CoV-2 infected human cell lines identifies HSP90 as target for COVID-19 therapy

Abstract

Detailed knowledge of the molecular biology of SARS-CoV-2 infection is crucial for understanding of viral replication, host responses and disease progression. Here, we report gene expression profiles of three SARS-CoV and SARS-CoV-2 infected human cell lines. SARS-CoV-2 elicited an approximately two-fold higher stimulation of the innate immune response compared to SARS-CoV in the human epithelial cell line Calu-3, including induction of miRNA-155. Single-cell RNA sequencing of infected cells showed that genes induced by virus infections were broadly upregulated, whereas interferon beta/lambda genes an pro-inflammatory cytokines such as IL-6 were expressed only in small subsets of infected cells. Temporal analysis suggested that transcriptional activities of interferon regulatory factors precede those of nuclear factor κB. Lastly, we identified heat shock protein 90 (HSP90) as a protein relevant for the infection. Inhibition of the HSP90 activity resulted in a reduction of viral replication and pro-inflammatory cytokine expression in primary human airway epithelial cells.

SARS-CoV-2-mediated dysregulation of metabolism and autophagy uncovers host-targeting antivirals

“…11e). As VeroFM cells are type I IFN-deficient and have limited expression of the entry co-factor TMPRSS2 29,53 , we further confirmed selected findings in human lung Calu-3 cells (Supplementary Fig. 11f).…”

“…1c, red) hint towards increased SAT1 activity, which is a known autophagy inducer 15 . Re-analyzed bulk and single-cell RNAsequencing datasets of Calu-3 cells 29 show increased SAT1 expression in SARS-CoV-2-infected cells (Supplementary Fig. 5c).…”

Host factors facilitating SARS‐CoV‐2 virus infection and replication in the lungs

“…Inhibition of S-protein fusion [ 330 , 331 ] LY6E Lymphocyte antigen 6E Restricts entry of corona viruses via interference of the S-protein fusion [ 332 , 333 ] ZAP Zinc finger antiviral protein Expressed in human lung cells, endogenous ZAP expression reduces SARS-CoV-2 replication in human lung cells. Targets CpG dinucleotides of SARS-CoV-2 [ 334 , 335 ] HSP90 Heat shock protein 90 Inhibition of HSP90 activity can reduce viral replication and pro-inflammatory cytokine expression in airway epithelia [ 336 , 337 ] APOBEC Apolipoprotein B mRNA editing enzyme catalytic polypeptide APOBEC protein family, together with tetherin and TRIM5a is part of the innate immunity against viral infections. Host-dependent genome editing of SARS-CoV-2 [ 338 – 340 ] …”

Versatile and flexible microfluidic qPCR test for high-throughput SARS-CoV-2 and cellular response detection in nasopharyngeal swab samples

“…Monitoring miRNAs expression levels in swabs or saliva during the course of infection might be of great interest, because of their stability in biological fluids and frequent alterations PLOS ONE during both chronic and acute airway infections [30,31]. For instance, small RNA profiling of in vitro SARS-CoV-2 infected cell lines resulted in an increased expression of miR-155, one of the miRNAs detected in our clinical samples (Fig 3C) [32]. This miRNA, frequently associated with virus infection, was recently shown to contribute to the development of lethal acute respiratory distress syndrome (ARDS) in H1N1 influenza A virus-infected mice, suggesting it could represent a valuable biomarker to follow the individual immune response of patients [33].…”