HCoV-229E Mpro Suppresses RLR-Mediated Innate Immune Signalling Through Cleavage of NEMO and Through Other Mechanisms

Area of Science:

• Immunology
• Virology
• Molecular Biology

Background:

• Mammals detect pathogens using pattern recognition receptors, including RIG-I-like receptors (RLR) crucial for antiviral innate immunity.
• Coronaviruses employ diverse strategies to evade RLR-mediated immune responses, often linked to severe disease.
• Immune evasion by common cold coronaviruses remains less understood compared to highly pathogenic strains.

Purpose of the Study:

• To investigate the innate immune evasion mechanisms of common cold human coronaviruses (HCoVs).
• To determine if the main protease (Mpro) of HCoV-229E antagonizes RLR-mediated antiviral signaling.
• To compare the immune evasion activities of Mpros from low-pathogenic and highly pathogenic coronaviruses.

Main Methods:

• Assessed the antagonist activity of HCoV-229E Mpro against interferon (IFN) and NF-κB signaling.
• Investigated the direct cleavage of NEMO by Mpros from HCoV-229E, HCoV-OC43, and MERS-CoV.
• Analyzed the impact of HCoV-229E Mpro on other RLR pathway components (MDA5, TBK1, IKKε).
• Monitored innate immune response and NEMO protein levels during HCoV-229E infection.

Main Results:

• HCoV-229E Mpro antagonizes IFN and NF-κB signaling by disrupting RLR pathways.
• Mpros from HCoV-229E, HCoV-OC43, and MERS-CoV directly cleave NEMO.
• HCoV-229E Mpro cleaves and/or degrades MDA5, TBK1, and IKKε.
• HCoV-229E infection results in delayed innate immunity and decreased NEMO levels, partly due to Mpro and cellular pathways.

Conclusions:

• The Mpro of common cold HCoV-229E actively suppresses innate antiviral immunity.
• Low-pathogenic coronaviruses share functional immune evasion strategies with highly pathogenic strains, including NEMO cleavage.
• Understanding these mechanisms is vital for comprehending coronavirus pathogenesis and host defense.