Scientists explore immunopathology of COVID-19

By Pooja Toshniwal PahariaReviewed by Aimee MolineuxMay 6 2022

In a recent review published in Immunological Medicine, researchers explored the interactions between severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and the host in the development of coronavirus disease 2019 (COVID-19).

Background

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

Hyperinflammation is caused due to the overexpression of several pro-inflammatory chemokines and cytokines - interferons (IFN) I and III, interleukins (IL)-1, 2, 6, 7, 10, 15, 17, 18, chemokines C-C motif ligands (CCL) 1, 2, 3, 4, 5, 6, 7, 8, 10, 20 and chemokine receptors. Hypercoagulation occurs due to elevation in fibrinogen, prothrombin, D dimer, factor VIII, von Willebrand Factor (vWF), platelet factor 4 (PF4), and an overreactive complement system.

SARS-CoV-2 faces several immunological barriers such as mucous secretions in the upper respiratory tract, that comprises anti-SARS-CoV-2 antibodies and antiviral proteins. The virus subsequently invades pulmonary tissues and can disseminate to other organs, based on COVID-19 severity.

Immune response to SARS-CoV-2 is based on the innate and adaptive immunity of the host. It involves activating signaling cascades that release antiviral substances and activate immune cells. The activation of B lymphocytes and T lymphocytes [cluster of differentiation (CD8 and CD4)] generate humoral/antibody-mediated and cell-mediated immune responses, respectively. The shift from innate to adaptive immune response occurs by antigen-presenting cells (APC) to T lymphocytes.

The immune profile of COVID-19 exhibits increased levels of cytokines, granzymes, perforins, neutrophils, monocytes (dendritic cells and macrophages), and decreased levels of lymphocytes and basophils. In addition, increased helper T (Th 1,17) responses and Th2-mediated B cell humoral responses with altered regulatory T cell levels are observed. Humoral immune responses comprise elevated secretory IgA (sIgA) antibodies and seroconversion of IgG and IgM in the early and late stages of COVID-19. T lymphocytes also differentiate into memory cells for combating reinfections.

Interactions between SARS-CoV-2 and the host

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

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

BK overexpression in COVID-19 is triggered by the kinin kallikrein system (KKS) and leads to the generation of desArg 9-BK (DABK) peptide. ACE and ACE2 inactivate BK and DABK, respectively. The increased 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, that expose the binding regions and thereby facilitate S-ACE2 binding.  SARS-CoV-2 binds specifically to the N-terminal domain (NTD) of ACE2 for viral fusion to host cell membranes, paving the way for genetic transfer to the host. The 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 enhanced by integrins (e.g β1 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 for activating S. In the case of TMPRSS insufficiency, viral S is activated by cathepsins L and B. After S cleavage, the ‘C-end rule’ (CendR) site of the virus interacts with NRP-1 to increase SARS-CoV-2 infectivity. Anosmia in COVID-19 could be due to NRP-1 overexpression in olfactory epithelial cells.

Disintegrin and metalloprotease 17 (ADAM-17) regulate levels of TNF-α, growth factors, cell adhesion molecules, and receptors. It detaches ACE2 into the soluble space to inhibit viral entry. 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 initial defense against SARS-CoV-2. The viral RNA and proteins act as pathogen-associated molecular patterns (PAMPs) and the corresponding substances secreted in response to cell damage or stress act as damage-associated molecular patterns (DAMPs). The DAMPs are identified by pattern recognition receptors (PRRs) such as TLR-2,3,4,7 that regulate TNF-α and IL-6 levels. Likewise, a retinoic acid-inducible gene I (RIG-I) limits viral replication by detecting viral RNA. The levels of IFN I, and III are regulated by the melanoma differentiation-associated protein 5 (MDA5) and laboratory of genetics and physiology 2 (LGP2) molecules, released on the activation of RIG-like receptors (RLRs).

SARS-CoV-2 activates nucleotide-binding oligomerization domain-containing protein 1 (NOD1) and NOD-like receptor containing pyrin domain 3 (NLRP3) leading to caspase 1-mediated IL-1β,18 overexpression. On PRR-mediated viral recognition, chemokines, interferons, and cytokines are secreted for viral eradication. PAMP-bound receptors interact with myeloid differentiation primary response protein 88 (MyD88) which interact with TLRs, TIR domain-containing adaptor-inducible interferon-b (TRIF), and mitochondrial antiviral signaling protein (MAVS). The proteins activate the NF-kb pathway and interferon regulatory transcription factors (IRF 3 and 7), for cytokine production.

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

Overall, the review elucidated the immunopathology of COVID-19 and highlighted several immunological molecules such as HS, TMPRSS2, IL6, DABK, and TLR4 that could be used as potential targets for SARS-CoV-2 therapeutics.