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The unfolded protein response (UPR) is a cascade of events that helps restoring cellular homeostasis under stressful conditions. It is activated when there is an imbalance in the protein load and protein folding capacity of the endoplasmic reticulum (ER) as a result of an increase in the naïve, unfolded, or misfolded protein content of the cell. Dengue virus (DENV) utilizes the host machinery to synthesize viral proteins and replicates in the cell. During DENV infection, up-regulation of viral proteins increases the protein pool of the cell, resulting in the induction of UPR pathway. In this study, we have tried to understand the consequence of UPR induction during DENV infection in human monocytic cells. To fulfill this objective, we have used VER-155008 (VER), a known inhibitor of the 78 kDa glucose-regulated protein (GRP78), which is the master regulator of the UPR pathway. After VER treatment, cells were infected with DENV, and the induction of the UPR elements and their downstream activation was studied by western blotting and RT-PCR analysis. Interestingly, inhibition of GRP78 via VER treatment led to the decreased expression of DENV envelope protein through the activation of the UPR elements, protein kinase-like ER resident kinase, activating transcription factor 6, and inositol-requiring enzyme 1 (IRE1), and then led to the activation of innate immune factors such as double-stranded RNA-activated protein kinase (PKR), interferon regulated factor 3 (IRF3), nuclear factor-κB (NF-κB) and interleukin 1β (IL-1β). This strategy may be used to decrease viral infection transiently. Thus UPR elements could be important therapeutic targets for decreasing DENV multiplication.

Recognition of virus infection by retinoic acid-inducible gene (RIG) I and melanoma differentiation-associated protein (MDA) 5, which are RNA helicases, and interferon-stimulated gene (ISG) 15 activates cascades of signal transduction pathways leading to production of type I interferons and proinflammatory cytokines that orchestrate the elimination of the viruses. However, it has been demonstrated that RNA-helicase-mediated innate immunity plays an essential role in defending the host from infection. In our efforts to identify plant-derived antivirals that selectively enhance ISG- and RNA-helicase-mediated antiviral immune responses, we identified a plant, rhodiola, that significantly promoted ISG, RIG-I and MDA 5 gene expression and an antiviral immune response against dengue virus (DENV) infection. Rhodiola induced interferon (IFN) β and other cytokines, including IL-1β, TNF-α, IL-6 and IL-8, in infected cells. It was also found that rhodiola upregulated phosphorylated eIF-2α, PKR and NF-kB in infected cells. In addition, the number of NK cells was also increased by rhodiola treatment in dengue-virus-infected human PBMCs. Treatment with a crude extract of rhodiola (RAE) resulted in effects in the 20 % range, which is similar to the magnitude of the same effects observed in DENV infections. Taken together, our results imply that rhodiola induces pharmacological modulation of RIG-I, MDA 5 and ISG signal transduction pathways in favor of the induction of a beneficial antiviral immune response against dengue virus, which can be a novel therapeutic strategy for management of infection.

The Alphaherpesvirinae include the neurotropic pathogens herpes simplex virus and varicella zoster virus of humans and pseudorabies virus of swine. These viruses establish lifelong latency in the nuclei of peripheral ganglia, but utilize the peripheral tissues those neurons innervate for productive replication, spread, and transmission. Delivery of virions from replicative pools to the sites of latency requires microtubule-directed retrograde axonal transport from the nerve terminus to the cell body of the sensory neuron. As a corollary, during reactivation newly assembled virions must travel along axonal microtubules in the anterograde direction to return to the nerve terminus and infect peripheral tissues, completing the cycle. Neurotropic alphaherpesviruses can therefore exploit neuronal microtubules and motors for long distance axonal transport, and alternate between periods of sustained plus end- and minus end-directed motion at different stages of their infectious cycle. This review summarizes our current understanding of the molecular details by which this is achieved.

The pathogenic mechanism of Dengue virus (DENV) infection is related to the host responses within target cells and therefore, we assessed intracellular changes in host cell proteins following DENV infection. This study provides evidence that heterogeneous nuclear ribonucleoprotein H (hnRNP-H) and protein disulfide isomerase A3 (PDIA3) helps in DENV multiplication by suppressing TNF-α production in human monocytic THP1 cells. Proteomic analysis of infected cells, identified upregulation of the host cell proteins PDIA3 and hnRNP-H in comparison to mock infected cells. The functional role of hnRNP-H and PDIA3 in DENV infection was identified by down regulating hnRNP-H and PDIA3 genes with their specific siRNA duplexes which lead to decreased intracellular viral load. It also resulted in increased TNF-α level which mediates antiviral effect. This is the first study, which reports the role of PDIA3 and hnRNP-H in TNF-α production in DENV infected cells. Collectively, these results suggest that increased level of hnRNP-H and PDIA3 expression in DENV infected THP1 cells assist in the viral replication by suppressing the TNF-α production.