Induction of UPR Promotes Interferon Response to Inhibit PRRSV Replication via PKR and NF-κB Pathway

Abstract

Porcine reproductive and respiratory syndrome virus (PRRSV) was previously shown to induce a certain level of cellular stress during viral replication. Unfolded protein response (UPR) is a cellular stress response responsible for coping with stress and cellular survival. However, the pathway leading to the induction of UPR that may influence PRRSV replication is still unknown. Here, we found that PRRSV infection induced UPR prior to interferon response. Induction of UPR significantly enhanced the expression of interferon and interferon-related genes, thus leading to the suppression of PRRSV infection. Next, we explored the underlying mechanisms of UPR-induced antiviral response. We found that induction of UPR promoted the expression of protein kinase R (PKR), and PKR was highly correlated with the reduction of PRRSV replication. Furthermore, tunicamycin stimulation and PKR overexpression activated NF-κB and interferon response at the early stage of PRRSV infection, thus reinforcing the expression of type I interferons and proinflammatory cytokines and leading to inhibition of PRRSV. In addition, PRRSV nsp4 was shown to reduce the expression of PKR. These findings might have implications for our understandings of the host’s immune mechanism against PRRSV and a new strategy of PRRSV to evade the host antiviral immunity.

DUSP1 mRNA modulation during porcine circovirus type 2 and porcine reproductive and respiratory syndrome virus co-infection regulates viruses replication

“…Nevertheless, the IFN-α/β mRNA expression remained significantly higher in co-infected cells than in PRRSV single-infected cells and mock-infected cells. This could explain the reduction in PRRSV replication observed in dually infected NPTr-CD163 cells in the present study, considering that type I interferons inhibit PRRSV replication ( Brockmeier et al., 2017 ; Zhu et al., 2021 ). Collectively, these results confirm that co-infection with both PCV2b and PRRSV differentially modulates cytokine transcriptional response in NPTr-CD163 cells compared to single-infected cells.…”

The Antiviral Compound PSP Inhibits HIV-1 Entry via PKR-Dependent Activation in Monocytic Cells

“…In recent years, studies on the interactions between UPR and PKR have surged with the purpose of promoting an anti-pathogenic environment. Among them, NF-κB signaling and production of type I IFNs have been researched to gain insights into their respective roles such as survivability and immune response [ 49 , 91 , 92 ]. Interestingly, a study has also shown that IRE1α directly activates PKR in response to Chlamydia trachomatis infection in a TLR4-dependent manner [ 50 ].…”

“…In a similar manner, it has been postulated that the interferon-induced protein (IFN-IP) double-stranded RNA-activated protein kinase (PKR) can interact directly with upstream regulators of cofilin-1 [ 47 , 48 ]. PKR has also been researched to be closely linked with the UPR [ 49 ]. Specifically, a study has shown the RNase activity of IRE1α can directly activate PKR downstream of TLR4 signaling [ 50 ].…”

HIV‐1 replication requires optimal activation of the unfolded protein response

“…It has been reported that PRRSV activates UPR. However, overstimulation of UPR by ER stress inducer activates the NF-κB and type-I Interferon response which leads to suppression of PRRSV infection [93,94]. Whereas another report has suggested that UPR induction by PRRSV particularly PERK facilitates viral replication by inducing autophagy and relieving stress [95].…”