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Impact of SARS-CoV-2 ORF6 and its variant polymorphisms on host responses and viral pathogenesis

Thomas Kehrer1, Anastasija Cupic1, Chengjin Ye2

  • 1Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.

Cell Host & Microbe
|September 22, 2023
PubMed

Insights

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) ORF6 protein hinders host immunity by blocking interferon signaling and mRNA export. Mutations in Omicron variants may reduce its immune evasion capabilities.

Area of Science:

  • Virology
  • Immunology
  • Molecular Biology

Background:

  • Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) utilizes accessory proteins to evade host immune responses.
  • The ORF6 protein is known to antagonize interferon signaling by interfering with nucleocytoplasmic transport.
  • The specific functions of ORF6 during active viral infection are not fully understood.

Purpose of the Study:

  • To investigate the role of SARS-CoV-2 ORF6 protein during physiological infection.
  • To elucidate the mechanisms by which ORF6 antagonizes host interferon responses and contributes to viral pathogenesis.
  • To analyze the impact of specific ORF6 mutations, such as D61L in Omicron variants, on immune evasion.

Main Methods:

  • Generation of recombinant SARS-CoV-2 viruses with ORF6 deletion or loss-of-function mutations.
  • Assessment of ORF6's impact on interferon signaling pathways.
  • Analysis of nucleocytoplasmic trafficking disruptions and transcription factor translocation (IRF, STAT).
  • Evaluation of cellular mRNA export inhibition and host proteome remodeling.
  • Characterization of viral protein expression regulation.
  • Investigation of the interaction between ORF6 and nuclear pore complex components (Nup98-Rae1).

Main Results:

  • ORF6 plays critical roles in antagonizing innate immunity and viral pathogenesis.
  • It interferes with nuclear import, specifically the translocation of IRF and STAT transcription factors.
  • ORF6 inhibits cellular mRNA export, leading to host proteome remodeling and regulation of viral protein expression.
  • The ORF6:D61L mutation, found in Omicron BA.2 and BA.4, shows reduced interaction with Nup98-Rae1, impairing immune evasion.
  • Recombinant viruses lacking functional ORF6 exhibit altered pathogenesis and immune antagonism.

Conclusions:

  • SARS-CoV-2 ORF6 is a key viral factor for antagonizing host innate immunity.
  • ORF6's disruption of nucleocytoplasmic transport and mRNA export is crucial for viral pathogenesis.
  • Specific mutations in ORF6 can modulate its immune evasion efficiency, impacting viral evolution.
  • Understanding ORF6 function is vital for developing effective antiviral strategies against SARS-CoV-2.
Keywords:
ORF6Omicron variantSARS-CoV-2SARS-CoV-2 pathogenesisinterferonmRNA exportnuclear importnucleocytoplasmic traffickingvirus-host interaction

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