Middle East Respiratory Syndrome Coronavirus-Encoded Accessory Proteins Impair MDA5-and TBK1-Mediated Activation of NF-��B

Abstract

Middle East respiratory syndrome coronavirus (MERS-CoV) is a newly emerging coronavirus which is zoonotic from bats and camels. Its infection in humans can be fatal especially in patients with preexisting conditions due to smoking and chronic obstructive pulmonary disease (COPD). Among the 25 proteins encoded by MERS-CoV, 5 accessory proteins seem to be involved in viral evasion of the host immune responses. Here we report that ORF4a, ORF4b, and ORF8b proteins, alone or in combination, effectively antagonize nuclear factor kappa B (NF-κB) activation. Interestingly, the inhibition of NF-κB by MERS-CoV accessory proteins was mostly at the level of pattern recognition receptors: melanoma differentiationassociated gene 5 (MDA5). ORF4a and ORF4b additively inhibit MDA5-mediated activation of NF-κB while that of retinoic acid-inducible gene 1 (RIG-I) is largely not perturbed. Of note, ORF8b was found to be a novel antagonist of MDA5-mediated NF-κB activation. In addition, ORF8b also strongly inhibits Tank-binding kinase 1 (TBK1)-mediated induction of NF-κB signaling. Taken together, MERS-CoV accessory proteins are involved in viral escape of NF-κB-mediated antiviral immune responses.

Nonstructural proteins NS7b and NS8 are likely to be phylogenetically associated with evolution of 2019-nCoV

“…In contrast, when we focused on MERS-CoV from bats and camels, ORF 8b antagonized melanoma differentiation-associated protein 5-mediated nuclear factor kappa B (NF-κB) activation. ORF 8b strongly inhibited TANK-binding kinase 1-mediated induction of NF-κB signaling, but not IκB kinase epsilon and IRF3-mediated activations (Lee et al, 2019a). Thus, we speculate that the properties of the accessory proteins, NS7b and NS8, in 2019-nCoV may affect its ability to infect humans.…”

Middle East Respiratory Syndrome-Coronavirus Infection into Established hDPP4-Transgenic Mice Accelerates Lung Damage Via Activation of the Pro-Inflammatory Response and Pulmonary Fibrosis

“…Next, we analyzed indicators of the inflammatory response in the tissues of hDPP4-Tg mice following MERS-CoV infection, because changes in cytokine and chemokine responses in patients severely infected with MERS-CoV are important aspects responsible for MERS-CoV pathogenesis (Fig. 4) [14,15,[25][26][27]. Specifically, using qRT-PCR, we determined the mRNA expression levels of the representative proinflammatory cytokines, IL-1β and TNF-α, as well as the chemokine, MIP-1α, which were selected based on previous in vivo studies of respiratory viral infections, including SARS-CoV [28,29].…”

Methyltransferase of a cell culture-adapted hepatitis E inhibits the MDA5 receptor signaling pathway

“…For luciferase assay, IFN-β-luc or NF-κB-luc was co-transfected with plasmids expressing an HEV-encoded gene and a host signaling molecule as indicated. DNA-PEI complex was generated by mixing at 1:2 ratio and incubating at RT for 30 min (Lee et al, 2019a(Lee et al, , 2019b(Lee et al, , 2019c. DNA-PEI complexes were added dropwise onto cells and cells were incubated for 24 h before harvested for luciferase reporter assay or western blotting.…”