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SARS-CoV-2 Accessory Protein ORF8 Targets the Dimeric IgA Receptor pIgR

Frederique Laprise1,2, Ariana Arduini1,3, Mathew Duguay1,4

  • 1Lady Davis Institute, Jewish General Hospital, Montreal, QC H3T 1E2, Canada.

Viruses
|July 27, 2024
PubMed

Insights

The SARS-CoV-2 virus uses its ORF8 protein to reduce the expression of a key immune receptor, polymeric Ig receptor (pIgR). This viral strategy helps SARS-CoV-2 evade the host

Area of Science:

  • Virology and Immunology
  • Molecular Biology
  • Respiratory Pathogens

Background:

  • SARS-CoV-2 infection targets the respiratory mucosa, but mechanisms of immune evasion are not fully understood.
  • Polymeric Ig receptor (pIgR) is crucial for mucosal immunity, transporting dimeric IgA (dIgA) and pentameric IgM (pIgM) to neutralize pathogens.
  • Reduced pIgR expression is observed in COVID-19 patients, suggesting a role in pathogenesis.

Purpose of the Study:

  • To investigate how SARS-CoV-2 antagonizes host mucosal immunity.
  • To identify SARS-CoV-2 proteins involved in downregulating pIgR expression.
  • To elucidate the role of ORF8 in SARS-CoV-2-mediated immune evasion at the mucosal level.

Main Methods:

  • Studied the interaction between SARS-CoV-2 proteins and pIgR.
  • Assessed the effect of viral proteins on pIgR expression levels.
  • Investigated the binding of ORF8 to cell surface pIgR and its functional consequences.

Main Results:

  • The viral accessory protein Open Reading Frame 8 (ORF8) was found to potently downregulate pIgR expression.
  • ORF8's downregulation of pIgR correlates with its interaction with the receptor, diminishing dIgA and pIgM binding.
  • ORF8 from variants of concern retains this pIgR downregulation activity, highlighting its conserved role in pathogenesis.

Conclusions:

  • SARS-CoV-2 ORF8 protein plays a significant role in antagonizing mucosal immunity by downregulating pIgR.
  • This conserved mechanism of immune evasion is important for SARS-CoV-2 pathogenesis.
  • ORF8's interaction with pIgR impairs the transport of protective antibodies, contributing to viral persistence.
Keywords:
IgAIgMORF8SARS-CoV-2mucosal immunitypIgR

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