Science, Medicine, and the Anesthesiologist

The heterogeneity in the clinical severity of COVID-19 requires immunologic analyses at the single-cell level to understand the relationships between variable immunologic responses and clinical outcomes.A multi-omics approach at single-cell resolution was applied to peripheral mononuclear cells from a cohort of 20 COVID-19 patients with varying disease severity.Upregulation of the pathway for receptor for advanced glycation end products (RAGE) was discovered on myeloid cells that correlated with disease severity.SARS-CoV-2 can enter myeloid cells despite the lack of expression of the angiotensin-converting enzyme 2 (ACE2), the prototypical receptor of SARS-CoV-2 binding.One theory is that SARS-CoV-2 may bind to RAGE in myeloid cells of COVID-19 patients.Computational in silico modeling predicted that the receptor binding domain of the S1 subunit of the spike protein of SARS-CoV-2 interacts with specific amino acid residues of RAGE.This was subsequently confirmed with purified proteins of RAGE and the spike protein, and these interactions were further confirmed by co-immunoprecipitation experiments in human peripheral monocytes.Azeliragon, an antagonist of RAGE, was shown to inhibit binding of purified spike proteins to a human monocytic cell line THP1, raising the possibility of a therapeutic approach to inhibiting SARS-CoV-2 binding to myeloid cells.(Article Selection: Charles Emala, M.D. Image: Adobe Stock.)Take home message: The receptor for advanced glycation end products (RAGE), a nonspecific multi-ligand pattern recognition receptor capable of binding a range of ligands, is an alternative entry pathway for SARS-CoV-2 in myeloid cells.Ligands that inhibit the RAGE receptor may allow novel therapeutics for COVID-19.