Immune regulation of the unfolded protein response at the mucosal barrier in viral infection

Wang, Ran; Moniruzzaman, Md.; Shuffle, Eric; Lourie, Rohan; Hasnain, Sumaira Z

Mucosal epithelial cells, due to their unique location with constant exposure to pathogens, activate different UPR pathways to adapt to the microenvironment and maintain homeostasis. ER stress and UPR activation are mechanisms by which mucosal epithelial cells combat viral infections. Viruses manipulate UPR and host protein synthesis machinery to favor replication. Rather than the chronic UPR activation provoked by inflammation, the UPR pathways are suppressed or bypassed by viruses. Viruses have adapted many ways to hijack the ER to replicate [57] [58] [59] and mimic host cytokines/cytokine receptors. 60 Synthesis of viral proteins often involves high levels of misfolding due to the high mutation rate, the unstable nature of viral genomes and extensive glycosylation of viral envelope proteins. 61 Moreover, along with viral protein misfolding, induction of ER Ca 2+ leakage, ER membrane rearrangement and modulation of intracellular glycoprotein trafficking have all been implicated in the UPR response. 62 Therefore, it is not surprising that viral infections often cause ER stress and activation of the UPR. 59, 63, 64 Viral modulation of the UPR Viruses have evolved mechanisms to modulate the UPR to either suppress or exacerbate already existing ER stress in order to maximise viral protein biosynthesis, and reduce or increase inflammation ( Figure 4 , Table 1 ). Viruses rely on the host ER and the ER stress response to replicate as viral replication is severely diminished in cell lines with mutations in ER-resident genes. 65 On the one hand, neither human cytomegalovirus nor West Nile virus, interestingly, induce canonical ER stress pathway via induction of XBP1-associated gene expression, rather they specifically trigger XBP1 for optimal cytokine production. 66 Hepatitis C virus, on the other hand, activates IRE1 but inhibits XBP1 and blocks eIF2a phosphorylation to prevent upregulation of ERAD machinery in order to establish persistency in infected hepatocytes. 57 Some viruses may selectively activate one arm of the UPR while suppressing other branches. Influenza A virus is found to selectively induce ATF6 translocation to promote caspase-12dependent cell apoptosis. 67 The respiratory syncytial virus (RSV) activates a non-canonical ER stress response with preferential activation of the IRE1 and activated ATF6 pathways without concomitant significant activation of the PERK pathway. 68 Autophagy is believed to be an ancient antiviral response. Upon evading the host, viral proteins can often be targeted by host autophagy pathway for lysosomal degradation, which promotes anti-viral innate and adaptive immunities via facilitating viral protein processing and presentation to antigen-presenting cells. 69 It is recognised now that the autophagy pathway can play both anti-viral and pro-viral roles in the pathogenesis of different viruses. Some viruses can utilise autophagy proteins to foster their own growth intracellularly. Under such conditions, autophagy pathways are often served as scaffold for viral entry or served as inter-cellular organelle to foster viral replication, suppressing innate immunity through insufficient viral protein presentation and preventing cell death. 70 The immune system has developed alternative ways to interrupt viral protein synthesis. These include upregulation of inflammatory cytokines, such as interferons, to reinforce cellular stress and autophagy response to combat viruses.