In a recent review published in immunological medicineresearchers investigated severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and host interactions in the development of coronavirus disease 2019 (COVID-19).
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COVID-19 disease is characterized by a hyperinflammatory and hypercoagulable state, which leads to pneumonia and severe acute respiratory syndrome (SARS), which increase morbidity and mortality in COVID-19 patients.
Hyperinflammation is due to overexpression of several 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 hyperresponsiveness of the system of the complement.
SARS-CoV-2 encounters several immunological barriers, such as mucosal secretions from the upper respiratory tract, which include anti-SARS-CoV-2 antibodies and antiviral proteins. The virus then invades lung tissue and can spread to other organs, depending on the severity of the COVID-19 infection.
The immune response to SARS-CoV-2 relies on host 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 through 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 reduced levels of lymphocytes and basophils. In addition, there is an increase in T helper responses (Th 1.17) and Th2-mediated humoral B cell responses, with impaired levels of regulatory T cells. Humoral immune responses include elevated 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 several organs such as the lungs (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. Reduced levels of APLN are associated with the progression of COVID-19. In contrast, elevated levels of histamines 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 triggered by the kinin-kallikrein system (KKS) and leads to the generation of the peptide desArg 9-BK (DABK). ACE and ACE2 inactivate BK and DABK, respectively. 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, which expose binding regions and thereby facilitate S-ACE2 binding. SARS-CoV-2 specifically binds to the N-terminal domain (NTD) of ACE2 for viral fusion to host cell membranes, thus 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 (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 to activate S. When TMPRSS is deficient, 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 the infectivity of SARS-CoV-2. COVID-19 anosmia might be due to overexpression of NRP-1 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 in the soluble space to inhibit virus 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 once morest 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 levels of TNF-α and IL-6. Similarly, a retinoic acid-inducible gene I (RIG-I) limits viral replication by sensing viral RNA. IFN I and III levels are regulated by melanoma differentiation-associated protein 5 (MDA5) and laboratory of genetics and physiology 2 (LGP2) molecules, released upon activation of RIG-like receptors (RLR).
SARS-CoV-2 activates nucleotide-binding oligomerization domain-containing protein 1 (NOD1) and pyrin 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-linked receptors interact with myeloid differentiation primary response protein 88 (MyD88) which 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 regulatory 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 action. Open reading frame proteins (ORFs 3a, 6, and 9b) inhibit IFN expression and STAT nuclear translocation, thereby limiting ISG expression.
Overall, this review elucidated the immunopathology of COVID-19 and highlighted several immunological molecules such as HS, TMPRSS2, IL6, DABK and TLR4 that might be used as potential targets for SARS therapeutics. -CoV-2.