A review study presented on the pathophysiology of the COVID-19 virus and found that entry and replication by the virus into cells expressing ACE 2 receptors triggers host cell pyroptosis, generating pro-inflammatory cytokines and chemokines which recruit monocytes, macrophages, and T-cells. This results in further inflammation and creation of a pro-inflammatory feedback loop, leading to overproduction of cytokines that accumulate in the lungs, causing a cytokine storm.

Review Investigating the Immunopathogenesis of COVID-19

A  European U-BIOPRED  (Unbiased BIOmarkers Predictive of REspiratory Disease outcomes) cohort study examined the mRNA expression level of ACE2, TMPRSS2, and Furin in the sputum, bronchial brush and bronchial biopsies of volunteer subjects.  These three biomarkers are heavily involved in the pathogenesis of COVID-19, and it was hypothesized that these expression levels would correlate with asthma severity or other molecular phenotypes.  These findings may help to explain why those with asthma and other respiratory diseases are more vulnerable to SARS-CoV-2 infection and symptoms of COVID-19.

Wide European Cohort Study That Examines Expression Levels of COVID-19 Susceptible Biomarkers in Patients with Severe Asthma

SARS-CoV-2 virions are surrounded by a lipid bilayer from which spike (S) protein trimers protrude. Heavily glycosylated S trimers bind the ACE2 receptor and mediate entry of virions into target cells. S exhibits extensive conformational flexibility: it modulates exposure of its receptor binding site and later undergoes complete structural rearrangement to drive fusion of viral and cellular membranes. 

The paper reports the application of cryo-electron microscopy and tomography to image intact SARS-CoV-2 virions, determining the high-resolution structure, conformational flexibility and distribution of S trimers in situ on the virion surface. These results reveal the conformations of S present on the virion, and provide a basis from which to understand interactions between S and neutralizing antibodies during infection or vaccination.

Structures and distributions of SARS-CoV-2 spike proteins on intact virions

Men present more frequently with severe manifestations of COVID-19 and are at higher risk for death, while studies from other viral infections have shown that females can mount stronger immune responses. The paper investigates the underlying mechanisms for these differences between female and male individuals infected with SARS-CoV-2.  

Emerging knowledge on the basic biological pathways that underlie differences in immune responses between women and men needs to be incorporated into research efforts on SARS-CoV-2 pathogenesis and pathology to identify targets for therapeutic interventions aimed at enhancing antiviral immune function and lung airway resilience while reducing pathogenic inflammation in COVID-19.

Implications of sex differences in immunity for SARS-CoV-2 pathogenesis and design of therapeutic interventions

Maucourant, C., Filipovic, I., Ponzetta, A., Aleman, S., Cornillet, M., Hertwig, L., Björkström, N. K. (2020). Natural killer cell immunotypes related to COVID-19 disease severity. Science Immunology, 5(50). doi:10.1126/sciimmunol.abd6832

Natural killer cell immunotypes related to COVID-19 disease severity

Several scientific studies investigate different molecular, clinical, and immunological aspects of the pathogenesis of COVID-19:

- **European Wide Cohort Study**: Examines expression levels of COVID-19 susceptible biomarkers (ACE2, TMPRSS2, Furin) in patients with severe asthma.
- **Review Investigating the Immunopathogenesis of COVID-19**: Explores how viral entry triggers pyroptosis, leading to a pro-inflammatory feedback loop and cytokine storms.
- **Structures and distributions of SARS-CoV-2 spike proteins on intact virions**: Analyzes the conformational flexibility and distribution of spike (S) trimers on intact virions.
- **Implications of sex differences in immunity**: Investigates the mechanisms underlying stronger immune responses in females compared to males.
- **Natural killer cell immunotypes**: Relates diverse NK cell phenotypes to COVID-19 disease severity.

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Retrospective epidemiological studies using clinical data and experimental molecular biologies studies have revealed biomarkers of COVID-19.  These elements not only reveal how COVID-19 mechanistically affects the body, but they may also be risk factors for developing severe symptoms and act as targets for pharmacological intervention.  They include:

- A1AT protection
- ACE2 expression and activity
- ADAM17 sheddase activity
- Furin protease activity
- Irregular respiratory function
- Pro-inflammatory cytokine concentration in the plasma
- TMPRSS2 serine protease genetic variation
- Variation in genetic susceptibility to SARS-CoV-2
- Viral interactions with glycosaminoglycans
- Nsp (Non-specific Protein) Activity
- Neuropilin-1 expression


Pathogenesis of COVID-19

TMPRSS2 is a human serine protease, an enzyme that cleaves a peptide chain via hydrolysis.  This enzyme has been shown to activate SARS-Cov-2 S protein by cleaving the S1 and S2 subunits of the S protein in order to expose the S2 subunit.  This allows the viral membrane to fuse with the cellular membrane.  Consequently, this process helps facilitate infection.  TMPRSS2 is also responsible for cleaving ACE2 receptors to further enhance SARS-CoV-2 entry.  This serine protease does not have a known, relevant function in human physiology and therefore could be a promising therapeutic target.  

TMPRSS2 in the Pathogenesis of COVID-19

SARS-CoV-2 S protein has two functional domains that regulate entry into a host cell:

- receptor binding domain (RBD)/ACE2 domain
- second domain (S2)

The S1 and S2 subunits of the S protein are connected by a polybasic furin cleavage site.  When furin acts on this site, the RBD and S2 domain are exposed which facilitate viral entry.    

Furin in the Pathogenesis of COVID-19

Studies Related to the Pathogenesis of COVID-19

Three primary observations have been made about ACE2 and its relation to SARS/COVID-19:

- ACE2 acts as a functional receptor for SARS-CoV-2 to enter host cells
- Increased ACE2 expression may elevate the risk of a SARS-CoV-2 infection as well as the development of COVID-19
- Reduced ACE2 expression may lead to acute respiratory distress syndrome

SARS‐CoV‐2 may be able to infect other tissues that express ACE2 using viral RNA that circulates in the blood.  

ACE2 in the Pathogenesis of COVID-19

Differences in COVID-19 inter-individual variability and lethality, along with differences among countries, raises the consideration of the role that predisposed genetics may play. Genetic variation may explain why some individuals without COVID-19 risk factors develop severe COVID-19.  Functional polymorphisms in the following genes are of interest due to their coded proteins' role in the pathogenesis of COVID-19:

- ACE2
- TMPRSS2

Understanding these variations in different populations could lead to more individualized treatment in COVID-19 patients.

Genetic Susceptibility to SARS-CoV-2 Infection in the Pathogenesis of COVID-19

Many viruses, including beta coronaviruses, have been shown to interact with human glycosaminoglycans, which are negatively-charged polysaccharides.  Studies suggest that SARS-CoV-2 can bind to the glycosaminoglycans heparan sulphate and heparin.  Additionally, it is thought. that heparin can prevent the virus from entering host cells while heparan sulphates facilitate infection by keeping SARS-CoV-2 S protein in its open conformation which allows it to interact with ACE2 receptors and TMPRSS2.

Glycosaminoglycans in the Pathogenesis of COVID-19

- Heparan sulfate proteoglycans are crucial for SARS-CoV-2 binding and infection 
- Low molecular weight heparins inhibit SARS-CoV-2 infection
- SARS-CoV-2 infection of epithelial cells is blocked by UF heparin and LMWH
- Heparan sulfates are required for transmission by primary dendritic cells
- Heparan sulfate proteoglycans Syndecan 1 and 4 are important for SARS-CoV-2 binding and infection.

 Heparan Sulfates and Low Molecular Weight Heparins in the Pathogenesis of COVID-19

While the mechanism remains unclear, it has been hypothesized that this type I sheddase transmembrane protein is involved in the pathogenesis of COVID-19.  Evidence that suggests that ADAM17 may be involved include:

- its known role in SARS-CoV viral uptake into host cells
- activating TNF‐α through cleave in cases of lung inflammation
- an association between high ADAM17 tissue expression and TNF‐α in an animal model of COPD, a known risk factor of COVID-19
- elevated ADAM17 gene expression in type II diabetic patients with diabetic low‐density lipoprotein (LDL)
- suggested contribution of ADAM17 to inflammation by stimulating IL-8 release
- proposed role in lung fibrosis and COPD through its ability to cleave IL-6R

ADAM17 in the Pathogenesis of COVID-19

A1AT is thought to be involved in the pathogenesis of COVID-19 because of its role as an innate immune system regulator, its function in lung homeostasis, and its potential relevance to the RAS system.  It may have a protective effect against SARS-CoV-2 infections by inhibiting the function of TMPRSS2 and TMPRSS2.  By inhibiting the serine protease ADAM17, which is involved in the viral uptake, the virus may be less efficient in infecting cells or may be prevented from infecting cells.  By inhibiting the sheddase ADAM17,  ACE2 cleavage would be controlled and may protect certain tissues from RAS system imbalance.  Additionally, inhibiting ADAM17 would prevent TNF‐α and IL6R cleavage which would have an anti-inflammatory effect which could ameliorate COVID-19 cytokine storm.  A1AT may also inhibit neutrophil elastase (NE), an enzyme that may be involved in SARS-CoV-2 S protein cleavage.  

A1AT in the Pathogenesis of COVID-19

In the innate immune response to SARS-CoV-2 infection, the host cells' pattern recognition receptors (PRR) recognise evolutionarily conserved molecular structures on the virus, called pathogen associated molecular patterns (PAMPS). When PAMPs bind to PRRs, the inflammatory response begins. PRRs activate several transcription factors to regulate the expression of genes responsible for inflammatory cytokine, interferon, chemokine, and adhesion molecule production.

Onset of Inflammatory Response in COVID-19

Nsp stands for non-structural protein. This group of proteins are found in the SARS-CoV-2 virus. The SARS-CoV-2 virus contains Nsp1-16. These Nsp proteins help the virus replicate once it reaches its host cell. Some non-specific proteins play a larger role in cell entry and viral replication than others. 


Nsp proteins that play a significant role in the viral replication of the SARS-CoV-2 virus:

- Nsp1 (Non-structural protein 1)
- Nsp3 (Non-structural protein 3)
- Nsp9 (Non-structural protein 9)
- Nsp12 (Non-structural protein 12)
- Nsp15 (Non-structural protein 15)

Nsp's (Non-structural proteins) in the Pathogenesis of COVID-19

Other Type II Transmembrane Serine Proteases in the Pathogenesis of COVID-19

SARS-CoV-2 can enter host cells using the Neuropilin-1 receptor, in addition to the ACE2 receptor. Neuropilin-1 is abundant in many human tissues, including the respiratory tract, blood vessels, and neurons. Because ACE2 is often expressed at very low levels on cell surfaces, the more abundant presence of Neuropilin-1 may be one of the factors that contributes to the rapid spread of the virus.

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