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

Detailed knowledge of the molecular biology of severe acute respiratory syndrome coronavirus 2 (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, a 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 kappa B. 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.

Automated summary

Detailed analysis of SARS-CoV-2 infection in comparison with SARS-CoV reveals a stronger induction of innate immune response, including the upregulation of miRNA-155. Infected cells show broad upregulation of genes, while interferon beta/lambda genes and pro-inflammatory cytokines like IL-6 are expressed in only a small subset of cells. Time analysis suggests that interferon regulatory factors are activated before nuclear factor kappa B in response to infection, with heat shock protein 90 (HSP90) identified as a relevant protein for viral replication and inflammatory cytokine expression.