Vaccinia virus Tiantan strain blocks host antiviral innate immunity and programmed cell death by disrupting gene expression

•Scientific questions: To our best knowledge, few systematic studies have reported the changes in host gene expression after vaccinia virus Tiantan (VTT) infection. This study aimed to reveal the dynamic process of reshaping the expression network of the host’s innate immune system at various stages of infection through time-series transcriptome analysis.•Evidence before this study: Studies on the host-virus interaction mechanism of vaccinia virus (VACV) based on the western reserve (WR) have revealed that the VACV suppresses the expression of host genes related to innate immunity. Infection of the replication-deficient modified vaccinia virus Ankara (MVA) strain can induce the type I interferon (IFN-I) pathway.•New findings: VTT and WR have similar gene expression patterns, widely suppressing host gene expression and regulating the expression of different host genes. VTT disrupts the host immune response to facilitate replication, underscoring the critical virus-host interactions in poxvirus infections.•Significance of the study: The outcomes of this study are significant for advancing our understanding of the interaction between the VTT and the host, enhancing the utilization of the VTT strain as novel viral vector or effective vaccine targeting smallpox and monkeypox. The vaccinia virus Tiantan (VTT) is widely utilized as a smallpox vaccine in China and holds significant importance in the prevention of diseases stemming from poxvirus infections. Nevertheless, few studies have investigated the influence of VTT infection on host gene expression. In this study, we constructed time series transcriptomic profiles of HeLa cells infected with both VTT and western reserve (WR) strains. We observed similar patterns of viral gene expression, while the expression levels of host genes varied between the two strains. There was an immediate and significant repression of host gene expression, particularly in genes associated with oxidative phosphorylation. Conversely, genes involved in nerve growth factor (NGF)-stimulated transcription were significantly activated. The upregulation of genes linked to the ribonucleic acid (RNA)-induced silencing complex (RISC) suggested a potential role for posttranscriptional regulation in the interaction between the vaccinia virus and the host. In the later stages of infection, pathways such as extracellular matrix organization, neutrophil degranulation, complement and interferon responses, translation, and programmed cell death are