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

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

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)

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

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

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


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- Affected organs and organ systems
- Circadian Physiology in relation to COVID-19
- Exercise/Physical Activity and COVID-19
- Immune response to COVID-19
- Laboratory methods
- Pathogenesis
- Patient comorbidities 
- Symptomology 
- Genetic mechanisms in COVID-19
- The body's response to stress hormones






Focuses of Human physiology studies on COVID-19

Rothan, H. A., & Byrareddy, S. N. (2020). The epidemiology and pathogenesis of coronavirus disease (COVID-19) outbreak. Journal of autoimmunity, 102433. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7127067/pdf/main.pdf
doi: 10.1016/j.jaut.2020.102433

The epidemiology and pathogenesis of coronavirus disease (COVID-19) outbreak

Klhůfek, J. (2020). The role of angiotensin-converting enzyme 2 in the pathogenesis of COVID-19: the villain or the hero?. Acta Clinica Belgica, 1-8. https://www.tandfonline.com/doi/full/10.1080/17843286.2020.1786324
doi: 10.1080/17843286.2020.1786324

The role of angiotensin-converting enzyme 2 in the pathogenesis of COVID-19: the villain or the hero?

Abassi, Z. A., Skorecki, K., Heyman, S. N., Kinaneh, S., & Armaly, Z. (2020). Covid-19 infection and mortality: a physiologist’s perspective enlightening clinical features and plausible interventional strategies. American Journal of Physiology-Lung Cellular and Molecular Physiology, 318(5), L1020-L1022.

https://journals.physiology.org/doi/full/10.1152/ajplung.00097.2020

https://doi.org/10.1152/ajplung.00097.2020

Covid-19 infection and mortality: a physiologist’s perspective enlightening clinical features and plausible interventional strategies

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

Partridge, L. J., Urwin, L., Nicklin, M. J., James, D. C., Green, L. R., & Monk, P. N. (2020). ACE2-independent interaction of SARS-CoV-2 spike protein to human epithelial cells can be inhibited by unfractionated heparin. bioRxiv.
https://www.biorxiv.org/content/10.1101/2020.05.21.107870v2
doi: 10.1101/2020.05.21.107870

ACE2-independent interaction of SARS-CoV-2 spike protein to human epithelial cells can be inhibited by unfractionated heparin

Udugama B, Kadhiresan P, Kozlowski H, Malekjahani A, Osborne M, Li V, Chen H, Mubareka S, Gubbay J, and Chan W

doi: 10.1021/acsnano.0c02624

Diagnosing COVID-19: The Disease and Tools for Detection

Schubert, K., Karousis, E.D., Jomaa, A. et al. SARS-CoV-2 Nsp1 binds the ribosomal mRNA channel to inhibit translation. Nature Structural & Molecular Biology (2020). https://doi.org/10.1038/s41594-020-0511-8.

SARS-CoV-2 Nsp1 Binds the Ribosomal mRNA Channel to Inhibit Translation

Pathogenesis of COVID-19

Current studies show that many organs that are heavily affected by COVID-19 have a high expression level of ACE2.

- Cardiovascular system
- Central nervous system (CNS)
- Gastrointestinal tract (GI)
- Kidney
- Liver 
- Lungs (Respiratory System)
- Peripheral nervous system (PNS)
- Testis

Organs and Organ Systems Affected by COVID-19

- Animal models
- Cell lines
- Genetically engineered SARS-CoV-2

Laboratory Methods in COVID-19 Research

Infection by SARS-CoV-2, as is with other viral infections, induces a two-phased immune response in the human body, described in the figure below: 
- Innate (rapid, natural, non-specific) 
- Adaptive (slow, acquired, specific)

Those two branches of the immune system cooperate with one another, and can be distinguished based on the cell-types involved (immune response vs white blood cells). However, the adaptive system is further broken down by the type of mechanism:

- Cell-mediated
- Antibody-mediated

Current research around COVID-19 immunity aims at uncovering the interaction between SARS-CoV-2 and the host's immune response, with questions related to pathogenesis, severity, and intervention.

Immune Response to COVID-19 

Presence and severity of symptoms of COVID-19 depend largely on individual characteristics. COVID-19 produces both symptomatic and asymptomatic infection.

Symptomology of COVID-19 

- Pituitary gland: improper functioning of the hypothalamus in association with pituitary gland; changes the metabolism of ADH (regulates the amount of water in the kidneys); abnormal sodium levels
- Thyroid: sick euthyroid syndrome → decrease in size of thyroid gland; changes in TSH levels
- Adrenal gland: increased chance of COVID-19 infection if presented with Cushing’s syndrome (too much cortisol) or Addison’s disease (inadequate aldosterone and cortisol)
- Pancreas: those with diabetes are at higher risk of getting COVID-19
- Bone: low vitamin D and hypocalcemia

Dysfunctions/ diseases in endocrine glands/organs that could lead to greater susceptibility to COVID-19

Exercise and physical activity induce physiological changes on many levels, the effects of which are best understood using a biopsychosocial approach.  The bidirectional relationship between exercise and Covid-19 can be further broken down into different components:
- Exercise/PA and COVID-19 by geographical location
- Exercise/PA and COVID-19 by demographics


Exercise/Physical Activity (PA) and Covid-19

COVID-19 comorbidities are high risk conditions that put patients at greater risk for infection and negative outcomes. Some COVID-19 comorbidities have been found to be: 
- Cancer 
- Cardiovascular Disease
- Diabetes
- Digestive Diseases
- HIV
- Hypertension
- Immunological Disease
- Liver Injury
- Obesity
- Renal disease
- Respiratory System Disease

COVID-19 Patient Comorbidities

Circadian biology refers to any biological process that has a rhythmic component dependent on time of day.  Understanding the relation between COVID-19 and circadian rhythm could help improve clinical management in treating COVID-19.

Circadian Physiology in relation to COVID-19

ARTICLES RESEARCHED
- Genetic mechanisms of critical illness in Covid-19
- Epigenetic dysregulation of ACE2 and interferon-regulated genes might suggest increased COVID-19 susceptibility and severity in lupus patients

Genetic mechanisms in COVID-19

Levels of stress may increase in those diagnosed with COVID-19, resulting in an alteration in stress hormone levels and the body's ability to cope with the stress.

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