Schuler et al. demonstrated using both mouse and human cell lines that TMPRSS2 expression increased with age.  The regulation of the enzyme during development could contribute to why infants and children are less susceptible to severe COVID-19.  Hou et al. writes that is will be important to study age-related polymorphisms of TMPRSS2 in the future using genetic epidemiology methods.

Age-Related Polymorphisms of TMPRSS2

Hou et al. proposed three different models for treating COVID-19 based on three different phenotypes which are found in different populations.  The following drugs were used in the models:

- hydroxychloroquine
- E-64D (a protease inhibitor)
- camostat mesylate (a TMPRSS2 inhibitor approved in Japan for treating chronic pancreatitis) 

These pharmacogenomic models have yet to be tested and validated.  

Hypothesized Combination Therapies to Treat COVID-19 Based on Pharmacogenomics

Because the incidence and mortality rates of COVID-19 are significantly different in different regions of the world, it is thought that human variation may play a greater role than viral variation in determining these outcomes.  Significant variation in the gene TMPRSS2, which codes for the protease TMPRSS2, has been observed in different ethnic groups.  This may contribute to the different rates of infectivity seen in different populations.  

Genetic variation within the TMPRSS2 protease may play a role in COVID-19 infection

This graphic shows the distribution of 61 potentially harmful ACE2 polymorphisms by population using variant assembly of databases, annotation of non-synonymous polymorphisms, and predictive-deleterious scoring. 
- databases: Genome Aggregation Database, Exome Sequencing Project, and 1000 Genomes Project (1KGP, www.internationalgenome.org)
- non-synonymous variant annotation: ANNOVAR
- deleterious assessment: CADD and Polyphen2 

The top bar shows ACE2 functional domains, and the vertical notches represents population counts of the respective variant. The heat map depicts polymorphism frequencies found within the different populations.

- 39% of variations occur in African/African-American (AFR) populations
- 54% of variations occur in non-Finnish European (EUR) populations
- Amish (AMI) and Ashkenazi Jewish (ASJ) populations do not appear to have any of these polymorphisms
- variants such as p.Arg514Gly may influence COVID-19 pathogenesis and its associated cardiovascular conditions by altering the AGT-ACE2 pathway

Population group legend: AFR, African/African-American; AMI, Amish; AMR, Latino/Admixed American; ASJ, Ashkenazi Jewish; EAS, East Asian; FIN, Finnish; EUR, Non-Finnish European; SAS, South Asian; PNA, population not assigned

Nonsynonymous ACE2 Variations by Population

This graphic shows the distribution of 63 potentially harmful TMPRSS2 polymorphisms by population using variant assembly of databases, annotation of non-synonymous polymorphisms, and predictive-deleterious scoring.

- databases: Genome Aggregation Database, Exome Sequencing Project, and 1000 Genomes Project (1KGP, www.internationalgenome.org)
- non-synonymous variant annotation: ANNOVAR
- deleterious assessment: CADD and Polyphen2

The top bar shows TMPRSS2 functional domains, and the vertical notches represents population counts of the respective variant. The heat map depicts polymorphism frequencies found within the different populations.

- 35% of variations occur in African/African-American (AFR) populations
- 59% of variations occur in non-Finnish European (EUR) populations
- all populations carry p.Val160Met (~25% allele frequency)
- p.Asp435Tyr, which codes for a key residue for the substrate binding of TMPRSS2, is only carried by non-Finnish European (EUR) populations
- if TMPRSS2 polymorphisms cause gene overexpression, Down Syndrome may be a risk-factor for COVID-19 due to TMPRSS2's localization on chromosome 21.

Population group legend: AFR, African/African-American; AMI, Amish; AMR, Latino/Admixed American; ASJ, Ashkenazi Jewish; EAS, East Asian; FIN, Finnish; EUR, Non-Finnish European; SAS, South Asian; PNA, population not assigned

Nonsynonymous TMPRSS2 Variations by Population

Allelic variants in the ACE2 gene has been observed in different ethinic populations, as well as in case-control studies within ethnic groups. However, these are present in relatively low frequencies. Functional studies are encouraged to characterize the relationship between ACE2 variants and COVID-19 severity, but no causal relationship can be made to date.

ACE2 variants and 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.

Michigan State University

Smith College

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

Hou, Y., Zhao, J., Martin, W., Kallianpur, A., Chung, M. K., Jehi, L., ... & Cheng, F. (2020). New insights into genetic susceptibility of COVID-19: an ACE2 and TMPRSS2 polymorphism analysis. BMC Medicine, 18(1), 1-8.
https://bmcmedicine.biomedcentral.com/articles/10.1186/s12916-020-01673-z

New insights into genetic susceptibility of COVID-19: an ACE2 and TMPRSS2 polymorphism analysis

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

- European Wide Cohort Study Examines Expression Levels of COVID-19 Susceptible Biomarkers in Patients with Severe Asthma
- Review Investigating the Immunopathogenesis of COVID-19
- Structures and distributions of SARS-CoV-2 spike proteins on intact virions
- Implications of sex differences in immunity for SARS-CoV-2 pathogenesis and design of therapeutic interventions
- Natural killer cell immunotypes related to COVID-19 disease severity

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

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

Researchers have found that COVID-19 virus is able to enter the body using another receptor, apart from ACE-2 receptor, called Neuropilin-1. This receptor is abundant in many tissues of the human body including respiratory tract, blood vessels and neurons. ACE-2 is expressed in very low levels on cell surfaces, the presence of Neuropilin in larger number may be one of the factor that attribute to its fast spread. 

Neuropilin-1 a receptor for COVID-19 entry 

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)

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