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.