TMPRSS2 As an Influential Human Gene for COVID-19


Sepideh Abdollahi 1 , Pantea Izadi 1 , *

1 Department of Medical Genetics, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran

How to Cite: Abdollahi S, Izadi P. TMPRSS2 As an Influential Human Gene for COVID-19. J Human Gen Genom. 2020;4(1):e119384. doi: 10.5812/jhgg.119384.


Journal of Human Genetics and Genomics: 4 (1); e119384
Published Online: November 19, 2021
Article Type: Review Article
Received: September 7, 2021
Accepted: November 3, 2021


In December 2019, the new virus, COVID-19, emerged and led to a pandemic respiratory acute disease. Almost all countries have experienced different rates of morbidity and mortality. These differences can be attributed to factors such as a diagnostic test capacity for COVID-19 and the health system efficiency. Besides the differences between countries related to the COVID-19 management, different patients represent a diverse range of clinical symptoms, from outpatient to patients admitted to the intensive care unit (ICU) due to the severity of symptoms. To gain deeper insights into such disparities in the severity of COVID-19 clinical presentations, epidemiological studies have reported risk factors such as old age, male sex, underlying chronic diseases such as diabetes, inflammatory and cardiovascular diseases, which have a bearing on susceptibility to COVID-19. In addition to these risk factors, the molecular mechanism involved in the virus entry process has been under investigation. Apart from a well-known protein called ACE2 (angiotensin-converting enzyme 2), which plays the receptor role for COVID-19, another essential protein in this pathway is TMPRSS2 (transmembrane protease, serine 2). This protease has a crucial role in effective membrane integration between the virus and the target cell. This process can affect the severity of the infection and the mortality rate of the disease. Thus, it seems that understanding the role of TMPRSS2 in COVID-19 infection can help better management by designing TMPRSS2 inhibitors drugs. Given the variants of the TMPRSS2 gene, which are associated with the severity of symptoms, people exposed to severe forms of this disease can be identified before the deterioration of the disease to adopt appropriate therapeutic approaches. Therefore, this study focused on the different levels of the TMPRSS2 interactions with COVID-19 virus and disease severity.

1. Context

In December 2019, China and a few months later, 184 other countries faced a global pandemic caused by SARS-CoV-2 (severe acute respiratory syndrome Coronavirus 2) or COVID-19, which is the main agent repressible for the spread of recent pneumonia (1, 2). COVID-19 is the seventh strain of the coronavirus and the fourth member of the betacoronaviridae family (3). Among coronavirus strains, 229E, HKU1, OC43 and NL63 have slight pathogenicity, while the SARS (severe acute respiratory syndrome) and MERS (Middle East respiratory syndrome) can lead to fatal pneumonia (4). The new strain of coronavirus, COVID-19, has a significantly higher transmission rate compared to other strains of this family (5). This substantial transmission rate has enabled the virus to spread to more than 184 countries and transforms into a pandemic as opposed to SARS and MERS, which only infected 29 and 27 countries, respectively (6, 7). According to the WHO (World Health Organization) as of 3 September 2021, there are 218,946,836 confirmed cases of COVID-19 disease and 4,539,723 deaths worldwide (8).

COVID-19 can be transmitted by mucus droplets of cough, sneeze, exhalation or physical contact from one person to another (9, 10). The common clinical symptoms of COVID-19 include shortness of breath or difficulty breathing, fever and chills, diarrhea or vomiting, body or muscle pain, sudden loss of taste and smell and unprecedented dizziness (11, 12).

The notable point about the clinical symptoms is that the severity and range of clinical symptoms vary from person to person. This difference can be attributed to risk factors such as old age, heart disease, diabetes, respiratory diseases, liver or kidney disease, obesity, smoking, pregnancy, use of immunosuppressive drugs, inflammatory chronic disorder, autoimmune diseases and male gender (13-17). However, the diversity of clinical symptoms in COVID-19, as in many other multifactorial diseases, can be influenced by the genetic background of individuals. Therefore, one of the interesting topics about COVID-19 is its genetic susceptibility. One approach to track the genes and variants that affect the disease severity is to study the molecular pathway of the COVID-19 virus entering cells, its replication and protein-encoding genes involved in this pathway (18-21). The first step to diagnose the entry of the COVID-19 virus into the cell is to identify cell surface receptor (ACE2) and membrane integration using the viral glycoprotein S (spike). As soon as the virus enters the host body, the S1 subunit of the S protein binds to the RBD (receptor-binding domain) and leads to the detection of the receptor, ACE2. On the other hand, the S2 subunit of S protein is involved in membrane integration, allowing the virus to enter the target cell (22, 23). It should be noted that apart from ACE2, another key component use by the virus for effective membrane integration is proteases on the cell surface such as TMPRSS2 (type 2 transmembrane serine proteases) (24). Furthermore, the virus uses the TMPRSS2 for the priming of its S proteins. This process of preparation and active entry is crucial for the success of the virus in inducing clinical symptoms and death (25). Thus, it is important to investigate the role of TMPRSS2 as a protein in the molecular process of COVID-19. In this way, the molecular mechanisms involved in the pathogenesis of COVID-19 and possible therapeutic targets can be clarified. All of these points can contribute to the management of this pandemic disease.

2. Results

2.1. TMPRSS2: From Gene to Protein and Its Function

TMPRSS2 or serine 2 translucent protease, is an enzyme encoded by the TMPRSS2 gene in humans. Located on chromosome 21q22.3, this gene contains 15 exons. It is expressed in various body tissues, including lungs, intestines, kidneys, pancreas and prostate. Also, the protein encoded by this gene has serine protease property (26, 27). The protease activity of this protein is attributable to active sites called H296, D345 and S441 in the S1 peptidase domain of the extracellular region. The extracellular region of this protein also contains SRCR-2 (scavenger receptor cysteine-rich domain 2) and LDLRA (LDL-receptor class A) domains in addition to the S1 peptidase domain (28, 29). (Figure 1). Regarding the function of TMPRSS2, it is worth noting that this protease, located on the surface of the host cell, has a pivotal role in the glycoprotein process of the virus (30). Moreover, the glycoprotein process is essential for the entry of the virus into the host cell (31). Thus, TMPRSS2 can influence the penetration of the virus into cells through the glycoprotein process. For instance, it has been reported that the cells of the host’s respiratory system are involved in the degradation of the influenza virus (hemagglutinin virus) by affecting the protease activity of TMPRSS2. Hemagglutinin degradation of this virus also is associated with the rate of infection caused by this virus and its tissue tropism (32, 33).

Figure 1. TMPRSS2 protein domains (TM, transmembrane domain; LDLRA, LDL-receptor class A, scavenger receptor cysteine-rich domain 2).

2.2. TMPRSS2: Molecular Mechanism Involved in the Entry of COVID-19 Into the Cells

COVID-19 penetrates cells through viral spike proteins (S proteins) by binding to its ACE2 receptors in target cells. Then S proteins are activated during the proteolytic process. The S proteins can be activated either through cathepsins, which leads to the virus entry in the cell through the endosomal pathway, or the protease property of TMPRSS2 protein on the surface of target cells, which leads to the entry of COVID-19 into the cell (34-36). According to a previous study, in human respiratory epithelial cells, circulating coronaviruses generally tend to enter cells via TMPRSS2 over the endosomal pathway (37). Also, TMPRSS2 has been involved in the proteolytic activity and activation of hemagglutinin influenza A virus (32), and it contributes to the spread of MERS-CoV infection by facilitating virus-cell attachment (38). Likewise, it is essential for the contraction of COVID-19 disease through the entry and membrane fusion of the COVID-19 virus by priming and activating S proteins (39). Another major point concerning TMPRSS2 is the SRCR domain, which contains a protected amino acid called valine 160. Previous studies have demonstrated the potential role of this amino acid in the binding of proteins, particularly proteins involved in the host’s defense system (28, 40, 41). These points exhibit that the role of TMPRSS2 is not limited to protease activity and it may be involved in the pathogenesis of COVID-19 virus by other mechanisms.

2.3. TMPRSS2: Gene Polymorphisms and Their Association to COVID-19

European populations have a higher rate of COVID-19 morbidity and mortality compared with East Asia populations. Comparison between these two populations regarding the variants and polymorphisms frequency of TMPRSS2 was carried out. The results showed the particular genetics variants of TMPRSS2 (rs463727, rs34624090, rs55964536, rs734056 rs4290734, rs34783969, rs11702475, rs35899679, rs35041537, rs2070788, rs9974589 and rs7364083), which can induce the higher expression of TMPRSS2 and are more frequent in European populations compared with East Asia (42). Moreover, another study has been reported SNPs, which can predict the expression of TMPRSS2 (43). Interestingly, the rs2070788 GG or rs383510 TT variant, which can lead to the overexpression of the TMPRSS2 in lung tissue, has been associated with increased susceptibility to influenza A (44). Maybe this association is related to the higher susceptibility of an individual to COVID-19 disease. However, the genetic variant of TMPRSS2, namely, p.V197M (p.Val197Met) (rs12329760), has a protective role in individuals against COVID-19 infection through its destructive effect on TMPRSS2 protease activity. This genetic variant is higher in individuals who have experienced milder clinical symptoms of COVID-19 (45). Therefore, it seems that by determining the polymorphisms in the TMPRSS2 gene, it is possible to identify the individual risk of infection and susceptibility to COVID-19. In this way, we can predict the disease process at early stages to make appropriate interventions.

2.4. TMPRSS2: Role in Gender Differences in COVID-19

According to the available evidence, the severity of the COVID-19 disease and its mortality rate is higher in men than in women (46-49). This gender difference in the severity of COVID-19 disease may be due to various behavioral habits and the degree of social exposure leading to virus transmission differences in males and females (50). Also, this difference could be induced by the effects of sex hormones, estrogen and androgens. Molecular studies on cancer have shown that testosterone, as a major androgen, affects the production of TMPRSS2 protein in the prostate glands of men which suffer from prostate cancer. Thus, TMPRSS2 gene appears to be an androgen-responsive gene (51, 52). It has been suggested that a similar mechanism may occur in the lung cells of men with COVID-19. In other words, TMPRSS2 is overexpressed under the influence of testosterone in men, which facilitates the entry of COVID-19 into the cell through its effect on viral S proteins. In this way, it produces various severities of the disease in men and women (53). On the other hand, in light of the importance of androgen-dependent TMPRSS2 in the entry of COVID-19 into the cell (54), studies have explored the use of TMPRSS2 inhibitors in preventing the virus from entering the cell by inhibiting the protease activity of TMPRSS2 (39, 55). Informed by these important points, extensive clinical studies have been conducted to investigate the effect of using TMPRSS2 inhibitors such as camostat, nafamostat and bromhexine on the controlling of severity of COVID-19 symptoms in patients (27, 54, 56). (Figure 2).

Figure 2. TMPRSS2 role in the process of COVID-19 entry to the target cell and contribution the androgens. Testosterone increases androgen receptor activity. Increased androgen receptor activity also increases transcription of the TMPRSS2 gene. COVID-19 uses ACE2 as a receptor to enter the cell and TMPRSS2 to prepare and activate its S proteins. Serine protease inhibitors such as camostat can partially block the entry of COVID-19 into cells by inhibiting TMPRSS2. (S1,2: spike glycoproteins).

2.5. TMPRSS2: Role in Age Differences in COVID-19

Evidence suggests that children and adults exhibit various degrees of clinical symptoms of COVID-19 disease (57). According to a study in China, 90% of children are either asymptomatic or experience a mild course of disease, but elderly patients are more likely to experience severe types of the disease and be hospitalized (58). Given the importance of TMPRSS2 in the infection rate of COVID-19, many studies have looked at the association between the expression of this gene and age in the respiratory epithelial cells. The investigations have revealed a positive correlation between the expression of the TMPRSS2 gene and age. According to the results, the expression of TMPRSS2 in nasal and bronchial tissue of children is significantly lower than that of adults. (59, 60). Considering that the entrance of COVID-19 into the cell depends on the expression of TMPRSS2 (39), it can be speculated that the mild clinical symptoms of COVID-19 in children could be affected by the lower levels of TMPRSS2 expression on the cell surface.

3. Conclusions

Today, the global pandemic of COVID-19 is affecting a large number of people in different countries across the world. Investigations regarding the molecular processes involved in COVID-19 entry into the cell and proliferation of the virus are crucial for better management of the disease. In this context, the critical interaction of TMPRSS2 with ACE2 as COVID-19 receptor has been highlighted, as it can determine the severity of consequences caused by COVID-19. Therefore, further studies on different and new aspects of the TMPRSS2 gene function and its association with the severity of COVID-19 disease can lead to the development of new drug targets for better management of this disease.



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