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SARS-CoV-2 ORF8 Mediates Signals in Macrophages and Monocytes through MyD88 Independently of the IL-17 Receptor

Nicole O Ponde1, Karsen E Shoger2, Mst Shamima Khatun3

  • 1Division of Rheumatology and Clinical Immunology, Department of Medicine, University of Pittsburgh, Pittsburgh, PA.

Journal of Immunology (Baltimore, Md. : 1950)
|June 2, 2023
PubMed

Insights

SARS-CoV-2 accessory protein ORF8 triggers inflammation in monocytes and macrophages. This signaling occurs via MyD88, independent of the IL-17 receptor, offering new insights into COVID-19 pathogenesis.

Area of Science:

  • Immunology
  • Virology
  • Molecular Biology

Background:

  • SARS-CoV-2 infection leads to severe COVID-19, with the ORF8 protein implicated in inflammatory responses.
  • Previous studies suggested ORF8 signaling in myeloid cells occurs through the IL-17 receptor complex (IL-17RA/RC).
  • IL-17 signaling is typically confined to non-hematopoietic cells due to limited IL-17RC expression.

Purpose of the Study:

  • To investigate the mechanism by which SARS-CoV-2 ORF8 protein induces cytokine expression in macrophages and monocytes.
  • To determine if ORF8 signaling in myeloid cells relies on the IL-17 receptor pathway.

Main Methods:

  • Analysis of IL17RC mRNA expression in monocytes/macrophages from SARS-CoV-2 infected human and mouse lungs.
  • Assessing cytokine gene expression in cultured mouse and human monocytes/macrophages stimulated with ORF8 or IL-17.
  • Evaluating ORF8-induced signaling in the presence of anti-IL-17RA/RC antibodies and in Il17ra-/- and Il1r1-/- cells.
  • Investigating the role of MyD88 adaptor protein in ORF8-mediated signaling.

Main Results:

  • IL17RC mRNA was undetectable in monocyte/macrophage populations in infected lungs.
  • ORF8, but not IL-17, significantly elevated target cytokine expression in cultured monocytes and macrophages.
  • ORF8 signaling remained intact in the absence of IL-17 receptor components (anti-IL-17RA/RC Abs, Il17ra-/- cells, Il1r1-/- cells).
  • Myeloid differentiation primary response 88 (MyD88) was essential for ORF8 activity, unlike IL-17 signaling.

Conclusions:

  • SARS-CoV-2 ORF8 protein induces inflammatory signaling in monocytes and macrophages.
  • ORF8 signaling in these myeloid cells is independent of the IL-17 receptor pathway.
  • ORF8 utilizes the MyD88 adaptor protein for signal transduction in monocytes and macrophages, distinct from IL-17R signaling.

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