Severe COVID-19 Pneumonia is Associated with Increased Plasma Immunoglobulin G Agonist Autoantibodies Targeting the 5-Hydroxytryptamine 2A Receptor
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Published on: December 19, 2020
1Veterans Affairs New Jersey Healthcare System, East Orange NJ, USA.
Aims:
To test whether plasma autoantibodies targeting the 5-hydroxytryptamine 2A receptor increase in COVID-19 infection; and to characterize the pharmacologic specificity, and signaling pathway activation occurring downstream of receptor binding in mouse neuroblastoma N2A cells and cell toxicity of the autoantibodies.
Methods:
Plasma obtained from nineteen, older COVID-19 patients having mild or severe infection was subjected to protein-A affinity chromatography to obtain immunoglobulin G fraction. One-fortieth dilution of the protein-A eluate was tested for binding to a linear synthetic peptide QN.18 corresponding to the second extracellular loop of the human 5-hydroxytryptamine 2A receptor. Mouse neuroblastoma N2A cells were incubated with COVID-19 IgG autoantibodies in the presence or absence of selective inhibitors of G-protein coupled receptors, signaling pathway antagonists, or a novel decoy receptor peptide.
Results:
5-hydroxytryptamine 2A receptor autoantibody binding occurred in 17 of 19 (89%) patients with acute COVID-19 infection and increased level was significantly correlated with increased severity of COVID-19 infection. The agonist autoantibodies mediated acute neurite retraction in mouse neuroblastoma cells by a mechanism involving Gq11/PLC/IP3R/Ca2+ activation and RhoA/Rho kinase pathway signaling occurring downstream of receptor binding which had pharmacologic specificity consistent with binding to the 5-HT2A receptor. A novel synthetic peptide 5-HT2AR fragment, SN..8, dose-dependently blocked autoantibody-induced neurotoxicity. The COVID-19 autoantibodies displayed acute toxicity in bovine pulmonary artery endothelial cells (stress fiber formation, contraction) and modulated proliferation in a manner consistent with known 'biased agonism' on the 5-HT2A receptor.
Conclusion:
These data suggest that 5-HT2AR targeting autoantibodies are highly prevalent may contribute to pathophysiology in acute, severe COVID-19 infection.
Insights
Autoantibodies targeting the 5-hydroxytryptamine 2A receptor (5-HT2AR) are prevalent in COVID-19 patients and correlate with disease severity. These autoantibodies contribute to neurotoxicity and endothelial cell dysfunction, suggesting a role in COVID-19 pathophysiology.
Area of Science:
- Neuroscience
- Immunology
- Virology
Background:
- COVID-19 infection can trigger autoimmune responses.
- The 5-hydroxytryptamine 2A receptor (5-HT2AR) plays a role in neurological function.
- Autoantibodies targeting specific receptors may contribute to disease pathology.
Purpose of the Study:
- To determine if autoantibodies against the 5-HT2AR increase during COVID-19 infection.
- To characterize the pharmacological specificity and signaling pathways activated by these autoantibodies.
- To assess the cytotoxic effects of these autoantibodies on neuronal and endothelial cells.
Main Methods:
- Plasma from COVID-19 patients was used to isolate immunoglobulin G (IgG) autoantibodies.
- Autoantibody binding to a 5-HT2AR peptide was assessed.
- Neuroblastoma cells were treated with autoantibodies to study neurite retraction and toxicity.
- Signaling pathway inhibitors and a decoy peptide were used to elucidate mechanisms.
Main Results:
- 89% of COVID-19 patients had 5-HT2AR autoantibodies, with levels correlating with disease severity.
- Autoantibodies induced neurite retraction via Gq11/PLC/IP3R/Ca2+ and RhoA/Rho kinase pathways.
- A synthetic peptide blocked autoantibody-induced neurotoxicity.
- Autoantibodies caused endothelial cell toxicity and exhibited biased agonism on 5-HT2AR.
Conclusions:
- 5-HT2AR autoantibodies are common in COVID-19 and may contribute to the pathophysiology of severe disease.
- These autoantibodies demonstrate specific binding and functional effects on neuronal and endothelial cells.
- Targeting 5-HT2AR with specific inhibitors could be a therapeutic strategy for COVID-19 complications.
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