Integrative Systems Immunology Analysis Reveals Elevated Anti-AGTR1 Levels with Accumulating COVID-19 Symptoms (preprint)

The coronavirus disease 2019 (COVID-19) displays a broad spectrum of symptoms, with the underlying reasons for this variability still not fully elucidated. Our study investigates the potential association between specific autoantibodies (AABs), notably those that targeting G protein-coupled receptors (GPCRs) and renin-angiotensin system (RAS) related molecules, and the diverse clinical manifestations of COVID-19, commonly observed in patients with autoimmune conditions, including rheumatic diseases, such as systemic sclerosis. In a cross-sectional analysis, we explored the relationship between AAB levels and the presence of key COVID-19 symptoms. Hierarchical clustering analysis revealed a robust correlation between certain AABs and symptoms such as fever, muscle ache, anosmia, and dysgeusia, which emerged as significant predictors of disease severity. Specifically, AABs against CHRM5 and CXCR3 were strongly linked to fever, while AABs against CHRM5 and BDKRB1 correlated with muscle ache. Anosmia was predominantly associated with AABs against F2R and AGTR1, while dysgeusia was linked to AABs against BDKRB1 and AGTR1. Furthermore, we observed a rise in AAB levels with the accumulation of these symptoms, with the highest levels detected in patients presenting all four predictors. Multinomial regression analysis identified AABs targeting AGTR1 as a key predictor for one or more of these core symptoms. Additionally, our study indicated that anti-AGTR1 antibodies triggered a concentration-dependent degradation of eGC, which could be mitigated by the AGTR1 antagonist Losartan. This suggests a potential mechanistic connection between eGC degradation, the observed COVID-19 symptoms, and rheumatic diseases. In conclusion, our research underscores a substantial correlation between AABs, particularly those against GPCRs and RAS-related molecules, and the severity of COVID-19 symptoms. These findings open avenues for potential therapeutic interventions in the management of COVID-19.

SARS-CoV-2 infection induces the production of autoantibodies in severe COVID-19 patients in an age-dependent manner (preprint)

Age is a significant risk factor for the coronavirus disease 2019 (COVID-19) outcomes due to immunosenescence and certain age-dependent medical conditions (e.g., obesity, cardiovascular disorder, diabetes, chronic respiratory disease). However, despite the well-known influence of age on autoantibody biology in health & disease, its impact on the risk of developing severe COVID-19 remains poorly explored. Here, we performed a cross-sectional study of autoantibodies directed against 58 targets associated with autoimmune diseases in 159 individuals with different COVID-19 outcomes (with 71 mild, 61 moderate, and 27 severe patients) and 73 healthy controls. We found that the natural production of autoantibodies increases with age and is exacerbated by SARS-CoV-2 infection, mostly in severe COVID-19 patients. Multivariate regression analysis showed that severe COVID-19 patients have a significant age-associated increase of autoantibody levels against 16 targets (e.g., amyloid beta peptide, beta catenin, cardiolipin, claudin, enteric nerve, fibulin, insulin receptor a, and platelet glycoprotein). Principal component analysis with spectrum decomposition based on these autoantibodies indicated an age-dependent stratification of severe COVID-19 patients. Random forest analysis ranked autoantibodies targeting cardiolipin, claudin, and platelet glycoprotein as the three most crucial autoantibodies for the stratification of severe elderly COVID-19 patients. Follow-up analysis using binomial regression found that anti-cardiolipin and anti-platelet glycoprotein autoantibodies indicated a significantly increased likelihood of developing a severe COVID-19 phenotype, presenting a synergistic effect on worsening COVID-19 outcomes. These findings provide new key insights to explain why elderly patients less favorable outcomes have than young individuals, suggesting new associations of distinct autoantibody levels with disease severity.

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome and Post-COVID Syndrome: A Common Neuroimmune Ground? (preprint)

A Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating chronic disease of unknown aetiology under growing interest now in view of the increasingly recognized post-COVID syndrome as a new entity with similar clinical presentation. We performed the first cross-sectional study of ME/CFS in community population in Russia and then described and compared some clinical and pathophysiological characteristics of ME/CFS and post-COVID syndrome as neuroimmune disorders. Of the cohort of 76 individuals who suggested themselves suffering from ME/CFS 56 subsequently were confirmed as having CFS/ME according to ≥1 of the 4 most commonly used case definition. Of the cohort of 14 individuals with post-COVID-19 syndrome 14 met diagnostic criteria for ME/CFS. The prevalence of clinically expressed and subclinical anxiety and depression in ME / CFS and post-COVID ME/CFS did not differ significantly from that in healthy individuals. Severity of anxiety / depressive symptoms did not correlate with the severity of fatigue neigther in ME / CFS nor in post-COVID ME/CFS, but the positive correlation was found between the severity of fatigue and 20 other symptoms of ME / CFS related to the domains of “post-exertional exhaustion”, “immune dysfunction”, “sleep disturbances”, "dysfunction of the autonomic nervous system", "neurological sensory / motor disorders" and "pain syndromes". Immunological abnormalities were identified in 12/12 patients with ME / CFS according to the results of laboratory testing. The prevalence of postural orthostatic tachycardia assessed by the active standing test was 37.5% in ME / CFS and 75.0% in post-COVID ME/CFS (the latter was higher than in healthy controls, p = 0.02) There was a more pronounced increase in heart rate starting from the 6th minute of the test in post-COVID ME/CFS compared with the control group. Assessment of the functional characteristics of microcirculation by laser doppler flowmetry revealed obvious and very similar changes in ME/CFS and post-COVID ME/CFS compared to the healthy controls. The identified pattern corresponded to the hyperemic form of microcirculation disorders, usually observed in acute inflammatory processes or in deficiency of systemic vasoconstriction influences.

Autoantibodies linked to autoimmune diseases associate with COVID-19 outcomes (preprint)

The SARS-CoV-2 infection is associated with increased levels of autoantibodies targeting immunological proteins such as cytokines and chemokines. Reports further indicate that COVID-19 patients may develop a wide spectrum of autoimmune diseases due to reasons not fully understood. Even so, the landscape of autoantibodies induced by SARS-CoV-2 infection remains uncharted territory. To gain more insight, we carried out a comprehensive assessment of autoantibodies known to be linked to diverse autoimmune diseases observed in COVID-19 patients, in a cohort of 248 individuals, of which 171 were COVID-19 patients (74 with mild, 65 moderate, and 32 with severe disease) and 77 were healthy controls. Dysregulated autoantibody serum levels, characterized mainly by elevated concentrations, occurred mostly in patients with moderate or severe COVID-19 infection, and was accompanied by a progressive disruption of physiologic IgG and IgA autoantibody signatures. A similar perturbation was found in patients with anosmia. Notably, autoantibody levels often accompanied anti-SARS-CoV-2 antibody concentrations, being both indicated by random forest classification as strong predictors of COVID-19 outcome, together with age. Moreover, higher levels of autoantibodies (mainly IgGs) were seen in the elderly with severe disease compared with young COVID-19 patients with severe disease. These findings suggest that the SARS-CoV-2 infection induces a broader loss of self-tolerance than previously thought, providing new ideas for therapeutic interventions.

The relationship between autoantibodies targeting GPCRs and the renin-angiotensin system associates with COVID-19 severity (preprint)

The coronavirus disease 2019 (COVID-19) can evolve to clinical manifestations resembling systemic autoimmune diseases, with the presence of autoantibodies that are still poorly characterized. To address this issue, we performed a cross-sectional study of 246 individuals to determine whether autoantibodies targeting G protein-coupled receptors (GPCRs) and renin-angiotensin system (RAS)-related molecules were associated with COVID-19-related clinical outcomes. Moderate and severe patients exhibited the highest autoantibody levels, relative to both healthy controls and patients with mild COVID-19 symptoms. Random Forest, a machine learning model, ranked anti-GPCR autoantibodies targeting downstream molecules in the RAS signaling pathway such as the angiotensin II type 1 and Mas receptor, and the chemokine receptor CXCR3 as the three strongest predictors of severe disease. Moreover, while the autoantibody network signatures were relatively conserved in patients with mild COVID-19 compared to healthy controls, they were disrupted in moderate and most perturbed in severe patients. Our data indicate that the relationship between autoantibodies targeting GPCRs and RAS-related molecules associates with the clinical severity of COVID-19, suggesting novel molecular pathways for therapeutic interventions.

Transcriptional landscape of SARS-CoV-2 infection dismantles pathogenic pathways activated by the virus, proposes unique sex-specific differences and predicts tailored therapeutic strategies (preprint)

The emergence of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) disease (COVID-19) has posed a serious threat to global health. As no specific therapeutics are yet available to control disease evolution, more in-depth understanding of the pathogenic mechanisms induced by SARS-CoV-2 will help to characterize new targets for the management of COVID-19. The present study identified a specific set of biological pathways altered in primary human lung epithelium upon SARS-CoV-2 infection, and a comparison with SARS-CoV from the 2003 pandemic was studied. The transcriptomic profiles were also exploited as possible novel therapeutic targets, and anti-signature perturbation analysis predicted potential drugs to control disease progression. Among them, Mitogen-activated protein kinase kinase (MEK), serine-threonine kinase (AKT), mammalian target of rapamycin (mTOR) and I kappa B Kinase (IKK) inhibitors emerged as candidate drugs. Finally, sex-specific differences that may underlie the higher COVID-19 mortality in men are proposed.