SARS-CoV-2 RNA stabilizes host mRNAs to elicit immunopathogenesis

Area of Science:

• Virology
• Molecular Biology
• Immunology

Background:

• Severe coronavirus disease 2019 (COVID-19) is driven by SARS-CoV-2 RNA interactions that suppress interferon responses and induce cytokine release.
• The precise mechanisms by which SARS-CoV-2 manipulates host RNAs to cause imbalanced immune responses are not fully understood.

Purpose of the Study:

• To investigate SARS-CoV-2 RNA structures and interactions with host factors in infected cells and patient samples.
• To elucidate how SARS-CoV-2 RNA binding influences host mRNA stability and immune signaling.
• To identify potential host targets for therapeutic intervention against COVID-19.

Main Methods:

• RNA interactions in situ were analyzed using RIC-seq in infected cells and patient lung samples.
• The role of RNA-binding protein YBX3 in mediating SARS-CoV-2 RNA-host mRNA interactions was investigated.
• Knockdown experiments and disruption of RNA duplexes were performed to assess functional consequences.

Main Results:

• SARS-CoV-2 RNA forms extensive duplexes with 205 host mRNAs, increasing their stability via YBX3 recruitment.
• Disrupting these RNA-RNA interactions or YBX3 knockdown reduced host mRNA stability and viral replication.
• The host gene NFKBIZ, stabilized by SARS-CoV-2, was found to promote cytokine production and suppress interferon responses, contributing to cytokine storm.

Conclusions:

• SARS-CoV-2 utilizes RNA-RNA interactions to stabilize host mRNAs, dysregulate immune responses, and promote severe COVID-19.
• YBX3 and specific host mRNA targets represent crucial players in SARS-CoV-2 pathogenesis.
• These findings highlight RNA-RNA interactions as a key mechanism in viral immunopathogenesis and offer potential therapeutic targets for drug development.