Abstract
Porcine circovirus type 2 (PCV2) infection induces autophagy and apoptosis. These cellular responses could be connected with endoplasmic reticulum (ER) stress. It remains unknown if PCV2 induces ER stress and if autophagy or apoptosis is primary to PCV2 infection or secondary responses following ER stress. Here, we demonstrate that PCV2 triggered unfolded protein response (UPR) in PK-15 cells by activating the PERK/eIF2α pathway without concomitant activation of IRE1 or ATF6. Since ATF4 and CHOP were induced later than PERK/eIF2α, it is clear that persistent PCV2 infection could lead to selective activation of PERK via the PERK-eIF2α-ATF4-CHOP axis. Therefore, PERK activation could be part of the pro-apoptotic signaling via induced expression of CHOP by PCV2. Since PERK inhibition by GSK2606414 or RNA silencing or suppression of eIF2α dephosphorylation by salubrinal limited viral replication, we suppose that PCV2 deploys UPR to enhance its replication. Over-expression of GRP78 or treatment with tauroursodeoxycholic acid could enhance viral capsid expression and/or viral titers, indicating that these chaperones, endogenous or exogenous, could help correct folding of viral proteins. Our findings provide the first evidence that ER stress plays a role in the pathogenesis of PCV2 infection probably as part of autophagic and apoptotic responses.
Highlights
Porcine circovirus type 2 (PCV2) is the primary causative agent of porcine circovirus-associated disease (PCVAD) [1]
A number of important issues remain to be addressed: Do the autophagic response and apoptosis occur independently during PCV2 infection? Is unfolded protein response (UPR) activated in PCV2-infected cells? Is UPR, once activated, linked with autophagy and/or apoptosis? The present study clearly shows that PCV2 induces UPR by activating the PERK pathway and employs PERK pathway and
We have previously shown that PCV2 infection can employ autophagy to enhance its replication in PK-15 cells [28]
Summary
Porcine circovirus type 2 (PCV2) is the primary causative agent of porcine circovirus-associated disease (PCVAD) [1]. Much progress has been made toward understanding the pathogenetic aspects of PCV2 infection, such as mechanisms of viral replication [8,9], epidemiology [10], clinical manifestations [11], host immune responses [12] and control strategies [13], there are still many important questions unanswered hitherto with regard to the pathogenesis of PCV2 infection. Apoptotic cell death could be one of the mechanisms of lymphoid depletion during PCV2 infection [14]. It remains unknown if apoptosis is the direct response of host cells to viral proteins such as ORF3 or capsid protein (Cap) [6,15] or indirect (or even secondary) host cell responses following autophagy or unfolded protein response (UPR). UPR, autophagy and apoptosis have been found to occur in succession in host cells undergoing persistent stresses via a number of common signaling mechanisms shared by these different cellular responses in deciding the cell fate [16]
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