Comparative Transcriptome Analysis Reveals the Intensive Early Stage Responses of Host Cells to SARS-CoV-2 Infection

Abstract

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused a widespread outbreak of highly pathogenic coronavirus disease 2019 (COVID-19). It is therefore important and timely to characterize interactions between the virus and host cell at the molecular level to understand its disease pathogenesis. To gain insights, we performed high-throughput sequencing that generated time-series data simultaneously for bioinformatics analysis of virus genomes and host transcriptomes implicated in SARS-CoV-2 infection. Our analysis results showed that the rapid growth of the virus was accompanied by an early intensive response of host genes. We also systematically compared the molecular footprints of the host cells in response to SARS-CoV-2, SARS-CoV, and Middle East respiratory syndrome coronavirus (MERS-CoV). Upon infection, SARS-CoV-2 induced hundreds of up-regulated host genes hallmarked by a significant cytokine production, followed by virus-specific host antiviral responses. While the cytokine and antiviral responses triggered by SARS-CoV and MERS-CoV were only observed during the late stage of infection, the host antiviral responses during the SARS-CoV-2 infection were gradually enhanced lagging behind the production of cytokine. The early rapid host responses were potentially attributed to the high efficiency of SARS-CoV-2 entry into host cells, underscored by evidence of a remarkably up-regulated gene expression of TPRMSS2 soon after infection. Taken together, our findings provide novel molecular insights into the mechanisms underlying the infectivity and pathogenicity of SARS-CoV-2.

Keywords: Calu-3 cell; SARS-CoV-2; host early response; time-series transcriptome; tmprss2.

FIGURE 1

Interaction between SARS-CoV-2 and cell host. (A) PCA of mock- and SARS-CoV-2 infected samples. (B) Read mapping rate to the host or virus genomes. (C) Activity distribution of virus genome over times. The y-axis is the relative sequencing depth that is normalized by (x-min)/(max-min) across the whole genome positions. Each line represents one biological replicate. (D) The numbers of DEGs at each time point among the three viruses. Only protein-coding genes were counted for SARS-CoV-2.

FIGURE 2

GO enrichment analysis of DEGs for the three viruses. The GO BP terms with enrichment FDR < 0.001 are shown.

FIGURE 3

Expression patterns of the host antiviral-related genes and cytokines. (A) Quantification of host antiviral capacity. (B) Expression patterns of the host antiviral-related genes. (C) Quantification of the host cytokine genes. (D) Expression patterns of the host cytokine genes.

FIGURE 4

Dynamic expression of four types of important genes. The value of the y-axis was restricted to have a maximum of 4 to show notable gene expression changes.

FIGURE 5

qRT-PCR validation of gene expression. The label “mock” indicates mock samples at 0 hpi. The labels from 0 to 24 h represent infected samples at indicated time points. Statistical significance is tested using t-test. “*” denotes significant difference and “ns” for no significance. The error bars represent mean ± SD. *p < 0.05, **p < 0.01, ***p < 0.001 and ****p < 0.0001.