MERS-CoV Accessory ORFs Play Key Role for Infection and Pathogenesis

Area of Science:

• Virology
• Immunology
• Pathogenesis

Background:

• Coronaviruses (CoVs) possess accessory open reading frame (ORF) proteins that, while not essential for replication, significantly impact infection and disease.
• Middle East respiratory syndrome coronavirus (MERS-CoV) outbreaks pose a global public health threat, necessitating research into its pathogenesis.

Purpose of the Study:

• To investigate the role of MERS-CoV accessory ORFs (ORF3, -4a, -4b, and -5) in viral pathogenesis and replication.
• To evaluate the potential of a MERS-CoV mutant lacking these accessory ORFs as a live attenuated vaccine.

Main Methods:

• Generation and characterization of a MERS-CoV mutant lacking all four accessory ORFs (dORF3-5).
• Assessment of viral replication and host responses *in vitro* and *in vivo*.
• Analysis of the role of ORF5 in modulating host inflammatory pathways, specifically NF-κB.

Main Results:

• The absence of MERS-CoV accessory ORFs (dORF3-5) significantly impairs viral replication and pathogenesis.
• Viral attenuation is primarily due to dysregulated host responses, including disrupted cellular processes, enhanced interferon pathway activation, and inflammation.
• The dORF3-5 mutant demonstrated *in vitro* and *in vivo* replication attenuation, supporting its use as a vaccine platform.
• ORF5 was found to play a partial role in modulating NF-κB-mediated inflammation.

Conclusions:

• MERS-CoV accessory ORFs are critical for pathogenesis, not just viral replication.
• The dORF3-5 mutant serves as a promising live attenuated vaccine candidate for MERS-CoV and related CoVs.
• Targeting accessory ORFs offers potential therapeutic strategies and a rapid response platform for future emergent coronavirus strains.