Classical swine fever virus Shimen infection increases p53 signaling to promote cell cycle arrest in porcine alveolar macrophages.

Aoxue Hu,Cunmei Gong,Pengbo Ning,Xuepeng Li,Congxia Hu,Xianghan Zhang,Yanming Zhang,Lifang Gao,Kangkang Guo,Yulu Zhou,Ya Zhang

doi:10.18632/oncotarget.18997

Abstract

Classical swine fever virus (CSFV) replicates in macrophages and causes persistent infection. Despite its role in disastrous economic losses in swine industries, the molecular mechanisms underlying its pathogenesis are poorly understood. The virus evades the neutralizing immune response, subverting the immune system to ensure its own survival and persistence. Our genome-wide analysis of porcine alveolar macrophage transcriptional responses to CSFV Shimen infection using the Solexa/Illumina digital gene expression system revealed that p53 pathway components and cell cycle molecules were differentially regulated during infection compared to controls. Further, we investigated the molecular changes in macrophages infected with CSFV Shimen, focusing on the genes involved in the p53 pathway. CSFV Shimen infection led to phosphorylation and accumulation of p53 in a time-dependent manner. Furthermore, CSFV Shimen infection upregulated cyclin-dependent kinase inhibitor 1A (p21) mRNA and protein. In addition, CSFV Shimen infection induced cell cycle arrest at the G1 phase, as well as downregulation of cyclin E1 and cyclin-dependent kinase 2 (CDK2). The expression of genes in the p53 pathway did not change significantly after p53 knockdown by pifithrin-α during CSFV Shimen infection. Our data suggest that CSFV Shimen infection increases expression of host p53 and p21, and inhibits expression of cyclin E1 and CDK2, leading to cell cycle arrest at the G1 phase. CSFV may utilize this strategy to subvert the innate immune response and proliferate in host cells.

Highlights

Macrophages play an important role in both innate and acquired immune responses [1]
The cell cycle pathway was differentially regulated in the classical swine fever virus (CSFV) Shimeninfected and control samples. These results suggested that upregulation of the p53 signaling pathway by CSFV Shimen in macrophages may mediate their response to infection by modulating the cell cycle
Macrophages are target cells for CSFV, and the migration and diffusion of macrophages in vivo is an important mechanism of infection for CSFV [14]

Summary

INTRODUCTION

Macrophages play an important role in both innate and acquired immune responses [1]. Initially, macrophages are required to kill microorganisms such as viruses when they enter the body [2]. Macrophages are often attacked during viral infection and become carriers of the virus, leading to chronic infection [3]. A cellular microenvironment that facilitates virus replication is essential for the establishment of CSFV infection [7]. Macrophages play a crucial role in protecting the host from viral infection, their protective activities are subverted by CSFV [8], which could cause persistent infection in pigs. Despite progress in CSFV pathogenesis research, the key mechanism by which CSFV subverts the immune system is still poorly understood. To investigate the mechanism of CSFV pathogenesis, we performed digital gene expression (DGE) profiling to identify key genes that regulate signaling pathways in macrophages during infection. We investigated the effects of viral infection on the genes involved in transformation related protein (Trp or p53) signaling and cell cycle progression in macrophages

RESULTS

DISCUSSION

MATERIALS AND METHODS