Abstract
As a key cellular transcription factor that plays a central role in cellular responses to a broad range of stress factors, p53 has generally been considered as a host cell restriction factor for various viral infections. However, the defined roles of p53 in pseudorabies virus (PRV) replication, pathogenesis, and host responses remain unclear. In the present study, we initially constructed a p53 overexpressing a porcine kidney epithelial cell line (PK-15) to detect the effect of p53 on PRV replication in vitro. The results show that viral glycoprotein B (gB) gene copies and the titers of virus were significantly higher in p53 overexpressing PK-15 cells than in PK-15 and p53 inhibitor treated p53 overexpressing PK-15 cells. A similar result was also found in the p53 inhibitor PFT-α-treated PK-15 cells. We then examined the effects of p53 on PRV infection in vivo by using p53-knockout (p53−/−) mice. The results show that p53 knockout not only led to significantly reduced rates of mortality but also to reduced viral replication and development of viral encephalitis in the brains of mice following intracranial inoculation. Furthermore, we examined the effect of p53 knockout on the expression of the reported host cell regulators of PRV replication in the brains of mice by using RNA sequencing. The results show that p53 knockout downregulated the interferon (IFN) regulator genes, chemokine genes, and antiviral genes after PRV infection. This finding suggests that p53 positively regulates viral replication and pathogenesis both in vitro and in vivo. These findings offer novel targets of intrinsic host cell immunity for PRV infection.
Highlights
Pseudorabies virus (PRV) belongs to the genus Varicellovirus in the subfamily Alphaherpesvirinae and it is the pathogen that causes porcine Aujeszky’s disease (AD) [1]
P53 is required for efficient viral replication of other viruses. p53 knockdown impairs the replication of herpes simplex virus 1 (HSV-1) and the associated viral pathogenesis of the central nervous system (CNS) of mice [10, 11]
Factors provide limited information on the intrinsic host cell regulators that may be involved in the facilitation of PRV infection
Summary
Pseudorabies virus (PRV) belongs to the genus Varicellovirus in the subfamily Alphaherpesvirinae and it is the pathogen that causes porcine Aujeszky’s disease (AD) [1]. The virus has a broad host range and can infect most mammals; pigs are the natural reservoir and the only animal that can survive PRV infection [1]. The tumor suppressor protein p53 is a major host cellular response protein to a broad range of stress factors such as viral infection through its modulation of cellular pathways, including innate immune control, host cell cycling, proliferation, DNA repair, and apoptosis [3,4,5]. The replication of various viruses is enhanced by the knockout or knockdown of p53 and inhibited by the overexpression of p53. P53 knockdown impairs the replication of herpes simplex virus 1 (HSV-1) and the associated viral pathogenesis of the central nervous system (CNS) of mice [10, 11]. It was reported that the replications of human cytomegalovirus (HCMV) and porcine circovirus type 2 were impaired by p53 knockdown [12, 13]
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