Cyclooxygenase-2 Facilitates Newcastle Disease Virus Proliferation and Is as a Target for Canthin-6-One Antiviral Activity

Chongyang Wang,Junru Wang,Haijin Liu,Na Li,Ruochen Hu,Jiangkun Dai,Uwe Schneider,Zengqi Yang,Ting Wang

doi:10.3389/fmicb.2020.00987

Abstract

Cyclooxygenase-2 (COX-2), one of the mediators of inflammation in response to viral infection, plays an important role in host antiviral defense system. But its role in Newcastle disease virus (NDV) proliferation process remains unclear. This study revealed that inhibition of COX-2 could benefit NDV proliferation and overexpression of COX-2 dose-dependently suppressed NDV proliferation. Overexpression of COX-2 also showed inhibitory effect on NDV-induced endoplasmic reticulum (ER)-stress and autophagy, also promoted the expression of antiviral genes. However, prostaglandin E2 (PGE2), the major product of COX-2, had indistinctive effects on NDV proliferation. At variant time point post viral infection, a tight regulation pattern of COX-2 by NDV was observed. Using inhibitors and siRNA against signaling molecules, the nuclear factor-κB (NF-κB) and melanoma differentiation-associated gene 5 (MDA5) were identified as critical factors for NDV induced COX-2 expression. Nonetheless, at late stage of NDV proliferation, substantial suppression of COX-2 protein synthesis could be detected, accompanied by a decrease in mRNA half-life. Furthermore, three C ring-truncated canthin-6-one analogs were used to activate COX-2 expression and showed inhibitory effect on NDV proliferation with the effective concentrations on μM level. Taken together, these results illustrated a novel NDV-regulated cellular mechanism and indicated that COX-2 is an important regulator of NDV proliferation which can serve as a potential target for anti-NDV agents.

Highlights

Newcastle disease (ND) is caused by the ND virus (NDV), which is a highly contagious pathogen among avian species causing huge economic losses in commercial and backyard poultry (Alexander, 2000)
NS-398 showed enhancing effect on Newcastle disease virus (NDV) proliferation in BHK-21 cell line (Supplementary Figure S1). These results indicated that COX-2 inhibitors dose-dependently enhanced NDV proliferation
We observed that inhibition of COX-2 expression was beneficial to NDV proliferation in DF-1 cells and BHK-21 cells

Summary

Introduction

Newcastle disease (ND) is caused by the ND virus (NDV), which is a highly contagious pathogen among avian species causing huge economic losses in commercial and backyard poultry (Alexander, 2000). During infection with NDV, viral RNA (vRNA) is sensed by pattern-recognition receptors (PRRs) such as the melanoma differentiation-associated gene 5 (MDA5), which belongs to the RIG-I-like receptor (RLR) family (Motz et al, 2013). The cyclooxygenase (COX) enzyme plays an important role as part of the pro-inflammatory response (Gilroy et al, 1999). The major functional isoform, COX-2, is reported to be associated with inflammation, cancer, autophagy, and viral infection (Gilroy et al, 1999; Zelenay et al, 2015; Dudek et al, 2016; Niranjan et al, 2018). COX-2 gene silencing and catalytic inhibition were shown to sufficiently suppress dengue virus (DENV) proliferation (Lin et al, 2017), which indicated the function of COX-2 to be diverse during infection of different viruses

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