Scientists investigate the immunopathology of COVID-19

In a recent review published in immunological medicineResearchers examined severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and host interactions in the development of coronavirus disease 2019 (COVID-19).

Study: Immunouniverse of SARS-CoV-2. Image Credit: CROCOTHERY/Shutterstock

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COVID-19 disease is characterized by a hyperinflammatory and hypercoagulable state, leading to pneumonia and severe acute respiratory syndrome (SARS), which increase morbidity and mortality in COVID-19 patients.

Hyperinflammation results from overexpression of various pro-inflammatory chemokines and cytokines – interferons (IFN) I and III, interleukins (IL)-1, 2, 6, 7, 10, 15, 17, 18, CC chemokines pattern ligands (CCL) 1, 2, 3, 4, 5, 6, 7, 8, 10, 20 and chemokine receptors. Hypercoagulation occurs due to elevation of fibrinogen, prothrombin, D-dimer, factor VIII, von Willebrand factor (vWF), platelet factor 4 (PF4) and hyperreactivity of the complement system.

SARS-CoV-2 encounters several immune barriers, such as mucosal secretions from the upper respiratory tract, including anti-SARS-CoV-2 antibodies and antiviral proteins. The virus then invades the lung tissue and, depending on the severity of the COVID-19 infection, can spread to other organs.

The immune response to SARS-CoV-2 is dependent on the host’s innate and adaptive immunity. It involves the activation of signaling cascades that release antiviral substances and activate immune cells. B-cell and T-cell activation [cluster of differentiation (CD8 and CD4)] generates humoral/antibody-mediated and cell-mediated immune responses, respectively. The switch from the innate immune response to the adaptive immune response occurs via antigen presenting cells (APCs) to T lymphocytes.

The immune profile of COVID-19 shows increased levels of cytokines, granzymes, perforins, neutrophils, monocytes (dendritic cells and macrophages) and decreased levels of lymphocytes and basophils. In addition, there is an increase in T helper responses (Th1.17) and Th2-mediated humoral B cell responses, with reduced levels of regulatory T cells. Humoral immune responses include increased secretory IgA (sIgA) antibodies and IgG and IgM seroconversion in early and late stages of COVID-19. T cells also differentiate into memory cells to fight reinfections.

SARS-CoV-2 and Host Interactions

Downregulation of angiotensin-converting enzyme 2 (ACE2) alters the balance of the renin-angiotensin system (RAS) and other ACE2-processed substances such as apelin and bradykinin (BK), resulting in an increase in angiotensin II (Ang II) levels . ACE2 is expressed by various organs such as the lung (especially type II cells of the alveolar epithelium), the heart, the intestines, the brain, the kidneys and the testes. This explains the spectrum of clinical manifestations observed in patients with severe COVID-19.

Apelin (APLN) is a ligand for the apelin receptor (APJ) and the APLN-APJ system regulates RAS, increases ACE2 levels and increases the production of protective cytokines. Decreased levels of APLN are associated with the progression of COVID-19. In contrast, elevated levels of histamine are associated with excess cytokines in COVID-19. In addition, endoplasmic reticulum aminopeptidases 1 and 2 (ERAP1 and ERAP2) also regulate RAS by converting Ang II to Ang III and IV to produce anti-inflammatory effects.

Overexpression of BK in COVID-19 is mediated by the quinine-kallikrein system (KKS) and leads to the formation of the peptide desArg 9-BK (DABK). ACE and ACE2 inactivate BK and DABK, respectively. Elevated BK levels are responsible for pulmonary edema and clinical cough in COVID-19 patients. DABK increases vascular permeability and inflammation.

The receptor binding domain (RBD) of the SARS-CoV-2 spike (S) protein undergoes structural conformational changes, revealing binding regions and thereby facilitating S-ACE2 binding. SARS-CoV-2 specifically binds to the N-terminal domain (NTD) of ACE2 for viral fusion with host cell membranes, opening the way for gene transfer to the host. Viral ribonucleic acid (RNA) assembles into structural proteins and is released extracellularly by exocytosis to enter another host cell, and thus viral replication continues to take place. Heparan sulfate (HS) is a co-receptor that enhances S-ACE2 binding. Viral invasion is also promoted by integrins (eg, 1-integrins), neuropilin receptor-1 (NRP-1) and CD147, CD209 and CD209L.

However, SARS-CoV-2 requires proteases such as transmembrane serine proteases (TMPRSS2,4) and furin to activate S. When TMPRSS is deficient, viral S is activated by cathepsins L and B. After S cleavage, the C terminus of the virus rule (CendR) site interacts with NRP-1 to increase SARS-CoV-2 infection. COVID-19 anosmia may be due to overexpression of NRP-1 in olfactory epithelial cells.

Disintegrin and metalloprotease 17 (ADAM-17) regulate the levels of TNF-α, growth factors, cell adhesion molecules and receptors. It releases ACE2 into the soluble space to inhibit the entry of viruses. Factors such as toll-like receptors (TLR) and Ang II type I receptor (AT1) regulate ADAM-17 expression.

Immune responses and signaling cascades in SARS-COV-2 infections.

Innate immunity is the first line of defense against SARS-CoV-2. Viral RNA and proteins act as pathogen-associated molecular patterns (PAMPs) and the corresponding substances secreted in response to cellular damage or stress act as damage-associated molecular patterns (DAMPs). DAMPs are identified by pattern recognition receptors (PRRs) such as TLR-2,3,4,7 which regulate the levels of TNF-α and IL-6. Similarly, a retinoic acid inducible gene I (RIG-I) limits viral replication by detecting viral RNA. IFN I and III levels are regulated by melanoma differentiation-associated protein 5 (MDA5) and laboratory genetics and physiology 2 (LGP2) molecules, which are released upon activation of RIG-like receptors (RLR).

SARS-CoV-2 activates nucleotide-binding oligomerization domain-containing protein 1 (NOD1) and pyrine domain-containing NOD-like receptor 3 (NLRP3), resulting in overexpression of IL-1β,18 mediated by caspase 1. During PRR-mediated viral recognition, chemokines, interferons and cytokines are secreted for viral eradication. PAMP-coupled receptors interact with myeloid differentiation primary response protein 88 (MyD88) that interacts with TLRs, adapter-inducible interferon-b containing the TIR domain (TRIF), and mitochondrial antiviral signaling protein (MAVS). These proteins activate the NF-kb pathway and the interferon-regulating transcription factors (IRF 3 and 7), for the production of cytokines.

IFNs activate the Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling pathway and IFN-induced genes (ISGs) for antiviral activity. Open reading frame proteins (ORFs 3a, 6 and 9b) inhibit IFN expression and STAT nuclear translocation, limiting ISG expression.

Overall, this review clarified the immunopathology of COVID-19 and highlighted several immunologic molecules such as HS, TMPRSS2, IL6, DABK, and TLR4 that could be used as potential targets for SARS therapies.

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