Pathogenic mechanisms of post-acute sequelae of SARS-CoV-2 infection (PASC)
- Department of Biochemistry & Molecular Biology, Howard University College of Medicine, United States
- Division of Lung Diseases, National Institutes of Health (NIH), National Heart, Lung and Blood Institute (NHLBI), United States
- Department of Pediatrics, Division of Critical Care, Columbia University Vagelos College of Physicians and Surgeons and New York - Presbyterian Morgan Stanley Children's Hospital, United States
- Division of Experimental Medicine, University of California, United States
- Department of Medicine, Joe R. and Teresa Lozano Long School of Medicine, University of Texas, United States
Figures
Figure 1
SARS-CoV-2’s entry into the respiratory system and its binding to ACE2 receptor produces a cascade of host responses ranging from chronic inflammation to endothelial dysregulation.
Tables
Table 1
Proposed molecular, pathobiological, and pathophysiological mechanisms related to Long COVID symptoms.
| Dysregulated system | Mechanism | Biological/molecular factor* | Signaling pathway | Reference |
|---|---|---|---|---|
| Autonomic | Autoimmune dysfunction of the autonomic nervous system; cardiovascular autonomic dysfunction (CVAD); post-intensive care syndrome (PICS); orthostatic intolerance (OI); syncope; postural orthostatic tachycardia syndrome (POTS)-like dysfunction; (ME/CFS)-like dysfunction; antinuclear antibodies | ↑Ganglionic, adrenergic, and muscarinic acetylcholine receptor antibodies ↑G-protein-coupled receptor autoantibodies | Sympathetic nervous system; cytokine storms; activation of renin–angiotensin system | Al-Kuraishy et al., 2021; Baig et al., 2020; Bisaccia et al., 2021; Escorihuela et al., 2020; Gunning et al., 2019; Li et al., 2020a; Nelson et al., 2019; Shaw et al., 2019; van Campen et al., 2020; Wu and Yang, 2020; |
| Cardiovascular | Myocardial hypertrophy; focal myocardial fibrosis; acute myocardial infarction; cardiac hypertrophy; endothelial dysfunction and coagulation activation; neutrophil extracellular traps (NETs); inflammation-coagulation (Factor XII); direct complement activation (inflammation) | ↑Thrombin ↓Plasmin ↓Fibrinolysis ↑ NT-proBNP ↑cTnI ↑Serum lactate dehydrogenase ↑Creatine kinase | Aryl hydrocarbon receptor (AhR) signaling through an IDO-Kyn-dependent pathway (hypoxia induction) | Baldi et al., 2020; Basso et al., 2020; Flores et al., 2019; Gao et al., 2020; Hanneman et al., 2022; Lala et al., 2020; Liu et al., 2020b; Mueller et al., 2021; Parohan et al., 2020; Puntmann et al., 2020; Shi et al., 2020; Wallentin et al., 2020 |
| Endocrine | Damage to thyroid gland; thyroiditis/thyrotoxicosis | ↓Thyroxin-3, ↑ACE2, ↑TMPRSS2 | The Th17 and the AGE/RAGE signaling pathways | Clarke et al., 2022; Lazartigues et al., 2020; Wei et al., 2007; Wu et al., 2021 |
| Endothelial | Endothelialitis; thromboembolism; endothelial glycocalyx damage | ↑sP-Sel, vWF, and D-dimer ↑ Endothelin-1 (ET-1) ↓ Angiotensin II ↑Proinflammatory cytokines and chemokines ↑Plasma heparinase | Bradykinin pathway | Buijsers et al., 2020; Flores et al., 2019; Mueller et al., 2021; Osburn et al., 2022; Scherbakov et al., 2020; Zha et al., 2022 |
| Gastrointestinal | Impaired barrier function; gut inflammation, altered serotonin metabolism and gut microbiota dysbiosis, Ruminococcus gnavus positively correlated with inflammatory markers; Clostridia was negatively correlated, fungal translocation leading to NF-κB activation and inflammation | ↑ Ruminococcus gnavus, ↑Fecal calprotectin ↑Plasma serotonin (5-hydroxytrytamine, 5-HT) | Interferon gamma (IFN-γ) signaling | Chandrashekhar Joshi and Pozzilli, 2022; Giron et al., 2022; Schultheiss et al., 2022 |
| Hematological | Vascular dysregulation; hypercoagulopathy; endothelialitis; hemostatic changes that leave the endothelium inflamed, pre-adhesive, and prothrombotic; thrombocytopenia, deep vein thrombosis | ↑Plasminogen activator inhibitor factor I (PAI) ↑Tissue factor (TF) ↑von Willebrand factor (vWF) ↑D-dimer ↓Hb ↑GM-CSF | p38 MAPK; Antibody-dependent cellular toxicity | Aird, 2007; Boisramé-Helms et al., 2013; Giustino et al., 2020; Hamming et al., 2004; Hamming et al., 2007; Hussman, 2020; Liu et al., 2020a; Rahman et al., 2021; Riphagen et al., 2020; Zachariah et al., 2020 |
| Immunological | Dysregulated and heightened immune system; prolonged inflammation leading to multiorgan dysfunction; cytokine release syndrome (CRS); Mast Cell Activation Syndrome (MCAS); neutrophil extracellular traps (NETs); pattern recognition receptors (PRRs) including Toll-like receptor (TLR); retinoic acid-inducible gene-I (RIG-I)-like receptors; oxidative stress | ↑IL-1β, IL-2, IL-6 ↑IL- 8, IL-10 ↑IL-IL-12, IL-17 ↑IL-18 ↑IFN-γ, NF-κB; ↑IFN-I and IFN-III ↑TNF, ↑CXCL-10, ↑p38 MAPK ↑JAKs and STATs ↑GM-CSF ↑TGF- β ↑ESR | JAK/STAT; Toll-like receptor pathways (TLR-3 and TLR 7/8); AKT/mTOR/MAPK pathway; FcyRIIA; NF-κB p65 and p38 MAPK, 1/2 (STAT1/2) pathway | Blanco-Melo et al., 2020; Feng et al., 2019; Guo and Thomas, 2017; Jose and Manuel, 2020; Li and Verma, 2002; O’Shea et al., 2015; Pablos et al., 2020; Ronco and Reis, 2020; Tarentino and Maley, 1975; Tay et al., 2020; Tergaonkar et al., 2005; Totura et al., 2015; Wirth and Scheibenbogen, 2021; Ye et al., 2020; Zhang et al., 2020; Zhao and Zhao, 2020 |
| Neurological | Neuro-inflammation; coagulopathy; micro-thrombosis; aberrant immune response; metabolic brain disorders; stroke; Guillain–Barré syndrome; hemodynamic and coagulation disorders; arrhythmia; nervous system damage | ↑IL-18, IL-6, and IL-8 ↑CCL-11 ↑Neurofilament light (NFL) ↑Glial fibrillary acidic protein (GFAP) | Humoral and retrograde neural signals; blood–brain barrier (BBB) | Awogbindin et al., 2021; Castanares-Zapatero et al., 2022; Dando et al., 2014; Fernández-Castañeda et al., 2022a; Fernández-Castañeda et al., 2022b; Frere et al., 2022; Holmes et al., 2021; Lauer et al., 2018; Matschke et al., 2020; Pan et al., 2020; Poon et al., 2015; Proal and VanElzakker, 2021; Sahin et al., 2022; Song et al., 2020 ; Tate et al., 2022; VanElzakker, 2013; Wostyn, 2021; Wu et al., 2020 |
| Pancreatic | Direct insulin resistance and beta cell damage; indirect autoimmunity inflammation; stress and steroid-induced hyperglycemia | ↑PKR, PERK, ISR via viral RNA and Cytokine storm, IRS ↑IL-6 and TNF-α ↓REST (RE1-silencing transcription factor) ↑Amylase and lipase ↑HLA ↑Propionic acid ↑Isobutyric acid | Insulin signaling pathway, ISR | Shin et al., 2022 |
| Renal | Glomerulopathy; microangiopathy | ↑ACE2 receptor, ↑IFN-I and IFN-III | Renin–angiotensin–aldosterone system (RAAS) disorders | Blanco-Melo et al., 2020; Hamming et al., 2004; Harmer et al., 2002; Nalbandian et al., 2021 Tay et al., 2020; Zou et al., 2020 |
| Respiratory | Pulmonary fibrosis; pulmonary thromboembolism; pneumonia; pulmonary vascular damage; cytokine release syndrome; dysbiosis (increased Staphylococcus cohnii and Pasteurella multocida); lipid metabolism; beta-oxidation; amino acid metabolism; and carbohydrate metabolism; hyperactivated T-lymphocytes and inflammatory macrophages; NETosis | ↑TNF-α, IL-1 ↑IL-IL-1β, IL-6 ↑IL-12 ↑MCP-1 ↑GM-CSF ↑CCL19 ↑CCR6 + Th17 ↑IL-8 (CXCL8) | Insulin/IGF signaling pathway Citrate cycle; respiratory electron transport chain; Th17 cell differentiation pathway | Ackermann et al., 2020; Budhraja et al., 2022; D’Errico et al., 2020; George et al., 2020; Griffin et al., 2020; Grosse et al., 2020; Jin et al., 2021; Jonigk et al., 2022; Kosuge et al., 2012; Medina-Enríquez et al., 2020; Morganstein et al., 2021; Sakr et al., 2020; Shin et al., 2022; Sidarta-Oliveira et al., 2020; Verdecchia et al., 2020; Xie et al., 2021; Yaméogo et al., 2011; Ye et al., 2020 |
| Multisystem Inflammatory Syndrome in Children (MIS-C) | Kawasaki disease; cardiac involvement with macrophage activation; persistent T-cell immune response; mucosal barrier breakdown | ↑IL-6 and IL-1Ra | ??? | Feldstein et al., 2020; Sadanandam et al., 2020 |
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*
↑ and ↓ arrows indicate increased and decreased levels, respectively, of biological and/or molecular factors.
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Pathogenic mechanisms of post-acute sequelae of SARS-CoV-2 infection (PASC)
eLife 12:e86002.
https://doi.org/10.7554/eLife.86002
