Proteins of the secretory pathway govern virus productivity during lytic gammaherpesvirus infection

Abstract

Background: Diseases caused by gammaherpesviruses continue to be a challenge for human health and antiviral treatment. Most of the commonly used antiviral drugs are directed against viral gene products. However, the emergence of drug-resistant mutations ma limit the effectiveness of these drugs. Since viruses require a host cell to propagate, the search for host cell targets is an interestin alternative. Methods: In this study, we infected three different cell types (fibroblasts, endothelial precursor cells and macrophages with a murine gammaherpesvirus and analysed the host cell response for changes either common to all or unique to a particular cell type using oligonucleotide microarrays. Results: The analysis revealed a number of genes whose transcription was significantly up- or down-regulated in either one or two of the cell types tested. After infection, only two genes, Lman1 (also known as ERGIC53) an synaptobrevin-like 1 (sybl1) were significantly up-regulated in all three cell types, suggestive for a general role for the virus life cycl independent of the cell type. Both proteins have been implicated in cellular exocytosis and transport of glycoproteins through the secre tory pathway. To test the significance of the observed up-regulation, the functionality of these proteins was modulated, and the effect on virus replication was monitored. Inhibition of either Lman1 or sybl1 resulted in a significant reduction in virus production. Conclusions: This suggests that proteins of the secretory pathway which appear to be rate limiting for virus production may represent new targets for intervention.

Role of the early secretory pathway in SARS-CoV-2 infection

“…LMAN2 (VIP36) and ERGIC1, two ERGIC53-like lectins, also interact with orf7 and nsp10, respectively ( Table 1 ). VIP36 has been shown to control transport of high-mannose proteins ( Gupta, 2012 ; Mages et al, 2008 ). Thus, it could be that CoV-2 takes advantage of ERp44- and lectin-dependent ER-to-Golgi transport processes to accumulate in the ERGIC for budding.…”

Antiviral activity of traditional medicinal plants from Ayurveda against SARS-CoV-2 infection

“…These pathways are known to perform crucial functions like neurotransmission, regulation of sense of vision, regulation of blood pressure, smell, taste, and pain, regulation of transport of bio-chemicals, glucose metabolism, cell proliferation, transcription, apoptosis, and cell migration adhesion, adaptation, cell survival, and receptor for pharmaceutical agents. Dysfunctioning of these pathways may affect the normal homeostasis and associated with conditions weakening of immune system, inflammation, auto-immune diseases, cancer and involved in various pathological events caused due to the virus infections (Keating & Striker, 2012 ; Londino et al, 2017 ; Mages et al, 2008 ; Meineke et al, 2019 ; Naderer & Fulcher, 2018 ; Paludan & Mogensen, 2001 ; Ye, 2013 ; Zhang et al, 2016 ). The patients infected with SARS-CoV-2 can develop symptoms like neurological complications (Guillain-Barre syndrome, encephalopathy, hemorrhagic encephalopathy, dizziness, myalgia anosmia, encephalitis, necrotising stroke, epileptic seizures, and rhabdomyolysis), loss of taste, increased cellular apoptosis, and high level of chemokines, and cytokines (Carod-Artal, 2020 ; Chen et al, 2020 ; Guzzi et al, 2020 ; Mehta et al, 2020 ; Zheng et al, 2020 ).…”

The Intracellular Cargo Receptor ERGIC-53 Is Required for the Production of Infectious Arenavirus, Coronavirus, and Filovirus Particles

“…Furthermore, in the case of the arenaviruses, targeting ERGIC-53 function with an antiviral could be expected to set up an ongoing immunizing therapy, as defective, but presumably immunogenic, viral particles would be released during the course of treatment. While ERGIC-53 represents a potential broad-spectrum antiviral target for arenaviruses, coronaviruses, and filoviruses, it may also be required for additional human pathogens, such as the New World hantaviruses, orthomyxoviruses, or retroviruses, based upon its conserved interaction with their GPs ( Figures 1 D, 1E, 3 I, 3J, and S1 I) ( Jäger et al., 2012 ), or for DNA viruses, based on the finding that a murine gamma herpes virus was negatively impacted by silencing of ERGIC-53 ( Mages et al., 2008 ). Based on our finding that JUNV propagation is impaired in cells from ERGIC-53 null individuals, future studies should also address whether exposure to rodent-borne viruses, such as the arenaviruses, has exerted a selective pressure to maintain ERGIC-53 mutations within the human population as a means to confer resistance to infection.…”