Severe COVID-19 Pneumonia is Associated with Increased Plasma Immunoglobulin G Agonist Autoantibodies Targeting the 5-HT2A Receptor

aliml

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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.


Severe COVID-19 Pneumonia is Associated with Increased Plasma Immunoglobulin G Agonist Autoantibodies Targeting the 5-Hydroxytryptamine 2A Receptor
 
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aliml

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Inverse Association between Serotonin 2A Receptor Antagonist Medication Use and Mortality in Severe COVID-19 Infection​


Abstract​

Advanced age and medical co-morbidity are strong predictors of mortality in COVID-19 infection. Yet few studies (to date) have specifically addressed risk factors associated with COVID-19 mortality in a high-risk subgroup of older US adults having one or more chronic diseases. Our hypothesis is that medications having ‘off-target’ anti-inflammatory effects may play a role in modulating the immune response in COVID-19 infection. We analyzed baseline risk factors associated with respiratory failure or death in 55 older adult US military veterans hospitalized for COVID-19 infection during (March-June 2020) the peak of the pandemic in New Jersey. Fifty-three percent (29/55) of patients experienced respiratory failure and thirty-one percent (17/55) died. In adjusted logistic regression analysis, baseline neutrophil to lymphocyte ratio (NLR) (P=0.0035) and body mass index (P=0.03) were significant predictors of the risk for respiratory failure. Age (P=0.05) and non-use (vs. use) of psychotropic medications having serotonin 2A receptor antagonist properties (odds ratio 5.06; 95% confidence intervals 1.18–21.7; P= 0.029) was each a significant predictor of an increased risk of death. There was a significant interaction effect of age and non-use (vs.. use) of psychotropic serotonin 2A receptor antagonist medications on the odds ratio (OR) for death (P=0.011). In selected, ventilator-dependent COVID-19 pneumonia patients treated with psychotropic serotonin 2A receptor antagonist medications to control agitation and ICU delirium, there was an apparent positive association between medication use and significant rise in the absolute lymphocyte count and decrease in the neutrophil: lymphocyte ratio. Taken together, these data are the first to suggest that certain psychotropic medications used in the treatment of chronic psychiatric illness and/or for acute delirium are inversely associated with mortality in severe COVID-19 infection by unknown mechanism which may involve (in part) immunomodulatory effects.

 

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