2021; 41(6): 568-576
Ann Lab Med 2021; 41(2): 129-138
Published online March 1, 2021 https://doi.org/10.3343/alm.2021.41.2.129
Copyright © Korean Society for Laboratory Medicine.
Role of Genetic Variants and Gene Expression in the Susceptibility and Severity of COVID-19
Departments of 1Biochemistry and 2Surgical Oncology, All India Institute of Medical Sciences, Jodhpur, India
Correspondence to: Prasenjit Mitra, M.D., MRSB, FACSc
Department of Biochemistry, All India Institute of Medical Sciences, Basni Industrial Area Phase-2, Jodhpur 342005, Rajasthan, India
*These authors contributed equally to this study.
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Since its first report in December 2019, coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has rapidly emerged as a pandemic affecting nearly all countries worldwide. As the COVID-19 pandemic progresses, the need to identify genetic risk factors for susceptibility to this serious illness has emerged. Host genetic factors, along with other risk factors may help determine susceptibility to respiratory tract infections. It is hypothesized that the ACE2 gene, encoding angiotensin-converting enzyme 2 (ACE2), is a genetic risk factor for SARS-CoV-2 infection and is required by the virus to enter cells. Together with ACE2, transmembrane protease serine 2 (TMPRSS2) and dipeptidyl peptidase-4 (DPP4) also play an important role in disease severity. Evaluating the role of genetic variants in determining the direction of respiratory infections will help identify potential drug target candidates for further study in COVID-19 patients. We have summarized the latest reports demonstrating that ACE2 variants, their expression, and epigenetic factors may influence an individual’s susceptibility to SARS-CoV-2 infection and disease outcome.
Keywords: Angiotensin-converting enzyme 2 (ACE2) variants, Transmembrane protease, Serine 2 (TMPRSS2), Epigenetics, COVID-19, SARS-CoV-2 infection
Coronavirus disease 2019 (COVID-19) emerged in Wuhan city, China, in December 2019. On January 12, 2020, the World Health Organization (WHO) named the causative virus as novel coronavirus (nCov); the virus was renamed on February 11, 2020, as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) by the international virus classification commission . During the initial days of the epidemic, various countries followed and implemented different testing strategies, based on the accessibility of diagnostic methods [2, 3]. COVID-19 causes respiratory illness that may range from a mild viral pneumonia to acute respiratory distress syndrome (ARDS) leading to multi-organ failure. The elderly population and individuals suffering from chronic illness have to be extra cautious, as the mortality rate is considerably high among these groups . The massive spread of the virus across countries within a few months of onset led the WHO to declare COVID-19 a pandemic. As of July 19, 2020, the total number of cases and deaths worldwide stood at 14,043,176 and 597,583, respectively .
SARS-CoV-2 is transmitted to lung epithelial cells through aerosols. Various immune cells in the body may also augment the infection; peripheral neutrophilia and lymphocytopenia significantly induce the immune response and cause deleterious ARDS, multi-organ dysfunction, and finally the death in some patients. Additionally, a sudden surge of pro-inflammatory cytokines may lead to fatal outcomes, indicating that cytokines are crucial in the pathophysiology of COVID-19 .
These findings have raised the question of whether genetic or epigenetic variation can be used to identify symptom susceptibility or severity in this disease. A review of a number of studies has suggested that genetic factors along with other risk factors can determine an individual’s susceptibility to respiratory tract infections . As angiotensin-converting enzyme 2 (ACE2) receptor on host cells acts as an entry point for SARS-CoV-2, it is hypothesized that the
Coronaviruses are members of the enveloped single-stranded RNA viruses that cause respiratory, enteric, and cardiovascular diseases in humans and animals. Various coronaviruses, such as NL63,
During earlier SARS outbreaks, studies demonstrated, in an autopsy series using culture techniques, viral isolation, and
ACE2 structure and function
ACE2 is an ACE homologue discovered in 2000. The
ACE2 has multiple roles including catalytic activities with specific substrates; it acts as a negative regulator of the renin-aldosterone system, B0 AT1 amino acid transporter, and receptor for coronaviruses (SARS-CoV) . ACE2 restricts the adverse effects of Ang II on profibrotic and vasoconstrictors. The hydrolysis of Ang II into Ang 1-7 decreases oxidative stress, and Ang 1-7 has counter regulatory mechanisms including antifibrotic and vasodilatory actions. Consequently, ACE2 disturbance leads to elevated Ang II levels and reduced heart function . ACE2 is active in several tissues and is widespread in the lungs, kidneys, heart, and testis. Low levels of
ACE2 as SARS-CoV-2 primary receptor
ACE2 variation and SARS-CoV-2 receptor binding domain
ACE2 utilization by SARS-CoV-2 can be explored to gain insights into the mechanism of restricting SARS-CoV-2 entry into host cells. Although ACE2 is expressed in most vertebrates, SARSCoV-2 cannot always utilize it as a receptor. The ability of SARSCoV-2 to utilize ACE2 was predicted by observing few essential single amino acid (AA) variant sites, which were found to be important for SARS-CoV-2 . Recent reports showed that SARSCoV-2 can utilize ACE2 expressed in humans, Chinese horseshoe bats, swine, and civets, but not that expressed in mouse . In another study, Qiu,
Structural basis for SARS-CoV-2 recognition
In SARS-CoV, receptor recognition and membrane fusion occur through the viral S glycoprotein, which is present on the surface. As soon as the virus enters the host, the trimeric S protein is split into two subunits, S1 and S2, followed by viral release of the S1 subunit for post-fusion confirmation. Subsequently, the S1 subunit binds with the peptidase domain of ACE2 via its RBD, whereas membrane fusion takes place via the S2 subunit. Once the S1 subunit binds to the ACE2 peptidase domain, a single cleavage site is exposed on S2, which is subsequently sliced by various host proteases. This mechanism is crucial for viral infection. The SARS-CoV-2 S protein can also take advantage of ACE2 for host infection in a similar manner.
ACE2 also serves as a chaperone for membrane trafficking of the AA transporter B0 AT1(SLC6A19). B0 AT1 is involved in sodium-dependent uptake of neutral AA in intestinal cells. With the stabilization of B0 AT1, the comprehensive structure of ACE2 in a dimeric assembly has been reported by high-resolution studies . Docking of the S protein trimer onto the structure of the ACE2 dimer together with the RBD of the S protein revealed that two S protein trimers bind to an ACE2 dimer simultaneously. Using a structure-based rational strategy, neutralizing antibodies or decoy ligands with greater affinities for either coronavirus S protein or ACE2 could be produced for viral infection treatment modalities .
ACE2 variants and their association with SARS-CoV-2
Recently, it was suggested that
ACE2 expression in individuals across different ethnicities
In East Asia, the viral infection has spread exponentially; older males, in particular, are more affected by SARS-CoV and the recent SARS-CoV-2 infection.
Consistently, the prevalence of expression quantitative trait loci (eQTL) that show higher
ACE2 expression associated with age and SARS-CoV infection
A different trend of
Transmembrane protease serine 2
In humans, the
TMPRSS2 can also cleave and activate the SARS-CoV-2 S protein during membrane fusion. This protease cleaves the SARS-CoV-2 receptor, the ACE2 carboxypeptidase, and ACE2 cleavage has been shown to augment viral entry into the various host cells . TMPRSS2 also serves as an activator of SARSCoV entry into the host cells via the same mechanism. It is mostly expressed in the epithelial cells of human lungs, absorptive enterocytes, and upper endothelial cells of the esophagus, and it activates influenza A virus and meta-pneumo virus in culture cells . The virus replication stage at which proteases cleave the viral glycoproteins in the plasma membrane varies between SARS-CoV and other viruses such as meta-pneumo virus and influenza A virus . In the influenza A virus and meta-pneumo virus, entry is enabled by TMPRSS2 making a simple cut in the cell membrane glycoprotein, whereas in SARSCoV-2, the S protein is cleaved after the receptor induces a few conformational changes in protease structure . Initially, the protease cleavage site in the S protein was predicted to be exposed after receptor binding; however, it was found to be located very near the C-terminal region of S protein . Further studies have reported that the S protein of mouse hepatitis virus type 2 (MHV-2) usually undergoes conformational changes in two phases, which are facilitated by progressive receptor binding and proteolysis, to be activated for fusion . The MHV-2 S protein was found to be similar to the SARS-CoV S protein. Fusion and effective cleavage, while the receptor binds to the target cells, is very tightly controlled. Premature proteolysis of the activating cleavage site is also prevented efficiently in this way .
Cellular factors required for SARS-CoV-2 entry might provide information regarding viral transmission. Thus, protease dependence of SARS-CoV-2 entry has been studied .
Endosome cysteine proteases cathepsin B/L (CatB/L) are employed for SARS-CoV-2 S protein priming in cells along with TMPRSS2 protease activity. Priming by TMPRSS2 is essential for viral entry and for further spread in the affected host, whereas CatB/L activity is non-essential. Various studies have indicated that SARS-CoV-2 infection rate is also affected by TMPRSS2 proteolytic activity, which raises questions regarding the residual S protein priming conducted by CatB/L. It is hypothesized that furin-mediated pre-cleavage at the S1/S2 site in virally infected cells allows protease dependent entry into these cells, similar to MERS-CoV . In addition, TMPRSS2 is required for homeostasis maintenance and various developmental changes and thus constitutes a drug target for future use. Importantly, TMPRSS2 protease activity is blocked by the serine protease inhibitor camostat mesylate.
Human trials have been recently approved in Japan for testing potential anti-pancreatitis agents; however, the condition is not associated with viral infection. These compounds and various others have been found to significantly increase antiviral activity and thus might be considered as an effective off-label treatment option for SARS-CoV-2-induced respiratory distress . A recent study has reported that using a purified soluble form of TMPRSS11a, receptor binding to the pseudo-typed SARS-CoV S protein significantly enhanced virus multiplication rate. In addition, proteolytic cleavage was shown to be similar to trypsin . A specific spatial orientation of the TMPRSS2 protease with respect to the SARS-CoV-2 S protein is a major factor underlying receptor binding. Additionally, receptor-bound S protein interaction with TMPRSS2 occurs in a specific spatial orientation at the cell surface resulting in inefficient cleavage of SARS-CoV-2 S protein and subsequent membrane fusion. Arginine and lysine residues within ACE2 AAs 697–716 have been predicted to be of prime importance for TMPRSS2-mediated cleavage and histone acetyltransferase activity. In addition, ACE2 needs to be processed for SARS-S-driven entry mediated by these proteases. TMPRSS2 increases SARS-S-entry, because it competes with metalloprotease A disintegrin and metalloprotease 17 for ACE2 processing .
In particular, two different haplotypes can be inferred from the GTEx frequency data :
the haplotype that is more regularly seen is the “European” haplotype that comprises SNVs rs463727, rs34624090, rs55964536, rs734056, rs4290734, rs34783969, rs11702475, rs35899679, and rs35041537. This haplotype was found to be co-expressed and co-regulated with an eQTL (rs8134378). The eQTL (rs8134378) for TMPRSS2 is located 13 kb upstream of an androgen responsive enhancer, possibly upregulating the gene in an androgen-specific manner . However, this haplotype was missing in the Asian population.
Three SNVs, rs2070788, rs9974589, and rs7364083, comprise another haplotype, which was found to have increased
Dipeptidyl peptidase-4 (DPP4)
DPP4 is a transmembrane glycoprotein. It is an ecto-peptidase that cleaves amino-terminal dipeptides causing T cell activation and hence functions in host cell immune-regulation against viral infections. It also functions as a binding protein and ligand of extracellular factors like collagen and fibronectin. DPP4 is expressed by the epithelial and endothelial cells of vessels, as well as by the kidneys, intestines, lungs, and smooth muscle cells of the vasculature. DPP4 accelerates lung inflammation and causes fatal respiratory distress in MERS-CoV infection. Both SARS-CoV-2 and MERS-CoV affect the lower respiratory tract and cause ARDS, thus suggesting a link between SARS-CoV-2 and DPP4.
Molecular interactions between SARS-CoV-2 and DPP4 have been studied via computational model-based docking and 3D structures of the SARS-CoV-2 S glycoprotein and human DPP4 . This model suggests a tight interaction between the S glycoprotein domains and DPP4 receptor. DPP4 binding residues K267, T288, A289, A291, L294, I295, R317, Y322, and D542 interact with the MERS-CoV S protein. The SARS-CoV-2 S1 domain has shown a similar -interaction with DPP4 suggesting that MERS-CoV and SARS-CoV-2 share similar pathways while interacting with host cells. Thus, DPP4 inhibitors, such as gliptins, could be used in COVID-19 patients to significantly reduce viral infection and multiplication rate, as well as reduce cytokine storm and inflammation in the lower airways .
Epigenetic aspects of immune response in SARS-CoV-2 infection
Macrophages and dendritic cells constitute key “hazard” signals among various cells of the innate immune system. These signals are stimulus-specific and cell-specific to ensure the onset of spatial and temporal responses. Such cell-specific signals are facilitated by cytokine, interleukin, and chemokine secretion or direct cell-cell communication. Consequently, their epigenetic ability to alter within minutes of a stimulus is not only important for rapid antiviral host response activation, but also necessary to maintain a sustained and specific defense response. It has been suggested that epigenetic regulation is accountable for virus entry priming and retention of this highly regulated host immune response over the initial activation wave .
Previous studies have focused on epigenetic aspects of the activation and formation of the innate and adaptive immune responses. The primary responsibility of the innate system is manifested via interferon and tumor necrosis factor genes. Interferons are effective mediators in preventing viruses from entering and activating the pathogenic immune response [61, 62]. Consequently, many viruses have possibly developed virulent mechanisms to counteract specific interferon-stimulated gene effectors . Interferons and immune responses are sensitive to epigenetic modifications through different epigenetic pathways . In contrast, interferon-stimulated genes generally show lower amounts of inducing histones, such as H3K4me3 and H4Ac, and lower RNA polymerase II occupancy . Further chromatin remodelers and transcription factors are needed for the initiation of transcription at these genes including ATP-dependent chromatin remodeling complex SWItch / sucrose non-fermentable (SWI / SNF) [66, 67].
Viruses have also developed various pathways to antagonize and disrupt epigenetic regulatory mechanisms, such as viral protein interference with host histone modification enzymes , chromatin remodeling machinery, and modified histones . Current epigenetic studies have focused on the effects of genetic processes on DNA, rather than emphasizing the role of the genetic code itself. Major areas of focus include chromatin remodeling, histone methylation, and many other processes that affect how transcription is initiated, as well as how DNA is packaged in cells. Recently, Pinto
Approximately 60% of mammalian genes are thought to be influenced by miRNAs, especially cancer, metabolism, development, and apoptosis regulatory pathways. Since the first viral miRNAs were discovered in the human Epstein-Barr virus (EBV) , nearly 320 viral miRNA precursors have been identified. Most of the characteristics of miRNA-regulated gene expression appear to be particularly beneficial for viruses. For example, viruses targeting specific human genes via viral miRNAs create a suitable environment for virus replication and survival. In addition, viral miRNAs constitute a potential escape from the host immune system, because the host itself produces the miRNAs in the same way. Recently, Sacar Demirci,
CONCLUSIONS AND FUTURE PERSPECTIVES
The rapid surge in COVID-19 cases and the lack of specific management guidelines to date highlight the urgency and importance of identifying genetic factors that may influence disease susceptibility and severity. At present, information regarding genetic variants of
SC and KS: Literature review and manuscript drafting and revision; PM: conceptualization and design, proofreading and editing, and critical revision; SM and PS: proofreading and supervision. All authors have read the manuscript and provided final approval.
CONFLICTS OF INTEREST
- Hong KH, Lee SW, Kim TS, Huh HJ, Lee J, Kim SY, et al. Guidelines for laboratory diagnosis of coronavirus disease 2019 (COVID-19) in Korea. Ann Lab Med 2020;40:351-60.
- Mitra P, Misra S, Sharma P. COVID-19 pandemic in India: what lies ahead. Ind J Clin Biochem 2020;35:257-9.
- Sung H, Roh KH, Hong KH, Seong MW, Ryoo N, Kim HS, et al. COVID-19 molecular testing in Korea: practical essentials and answers from experts based on experiences of emergency use authorization assays. Ann Lab Med 2020;40:439-47.
- Mitra P, Suri S, Goyal T, Misra R, Singh K, Garg MK, et al. Association of comorbidities with coronavirus disease 2019: a review. Ann Natl Acad Med Sci (India) 2020;56:102-11.
- WHO. Coronavirus disease (COVID-19) dashboard. https://covid19.who.int (Updated on Jul 2020).
- Lingeswaran M, Goyal T, Ghosh R, Suri S, Mitra P, Misra S, et al. Inflammation, immunity and immunogenetics in COVID-19: a narrative review. Indian J Clin Biochem 2020;35:260-73.
- Lacoma A, Mateo L, Blanco I, Méndez MJ, Rodrigo C, Latorre I, et al. Impact of host genetics and biological response modifiers on respiratory tract infections. Front Immunol 2019;10:1013.
- Benetti E, Tita R, Spiga O, Ciolfi A, Birolo G, Bruselles A, et al. ACE2 gene variants may underlie interindividual variability and susceptibility to COVID-19 in the Italian population. Eur J Hum Genet 2020:1-13.
- Chen YY, Zhang P, Zhou XM, Liu D, Zhong JC, Zhang CJ, et al. Relationship between genetic variants of ACE2 gene and circulating levels of ACE2 and its metabolites. J Clin Pharm Ther 2018;43:189-95.
- Patel SK, Wai B, Ord M, MacIsaac RJ, Grant S, Velkoska E, et al. Association of ACE2 genetic variants with blood pressure, left ventricular mass, and cardiac function in Caucasians with type 2 diabetes. Am J Hypertens 2012;25:216-22.
- Zhang SF, Tuo JL, Huang XB, Zhu X, Zhang DM, Zhou K, et al. Epidemiology characteristics of human coronaviruses in patients with respiratory infection symptoms and phylogenetic analysis of HCoV-OC43 during 2010-2015 in Guangzhou. PLoS One 2018;13:e0191789.
- Hu B, Ge X, Wang LF, Shi Z. Bat origin of human coronaviruses. Virol J 2015;12:221.
- Pyrc K, Berkhout B, van der Hoek L. The novel human coronaviruses NL63 and HKU1. J Virol 2007;81:3051-7.
- Devaux CA, Rolain JM, Raoult D. ACE2 receptor polymorphism: susceptibility to SARS-CoV-2, hypertension, multi-organ failure, and COVID-19 disease outcome. J Microbiol Immunol Infect 2020;53:425-35.
- Ye J, Zhang B, Xu J, Chang Q, McNutt MA, Korteweg C, et al. Molecular pathology in the lungs of severe acute respiratory syndrome patients. Am J Pathol 2007;170:538-45.
- To KF, Tong JH, Chan PK, Au FW, Chim SS, Chan KC, et al. Tissue and cellular tropism of the coronavirus associated with severe acute respiratory syndrome: an in-situ hybridization study of fatal cases. J Pathol 2004;202:157-63.
- Nicholls JM, Poon LL, Lee KC, Ng WF, Lai ST, Leung CY, et al. Lung pathology of fatal severe acute respiratory syndrome. Lancet 2003;361:1773-8.
- Hamming I, Timens W, Bulthuis ML, Lely AT, Navis G, van Goor H. Tissue distribution of ACE2 protein, the functional receptor for SARS coronavirus. A first step in understanding SARS pathogenesis. J Pathol 2004;203:631-7.
- Tipnis SR, Hooper NM, Hyde R, Karran E, Christie G, Turner AJ. A human homolog of angiotensin-converting enzyme. Cloning and functional expression as a captopril-insensitive carboxypeptidase. J Biol Chem 2000;275:33238-43.
- Patel VB, Zhong JC, Grant MB, Oudit GY. Role of the ACE2/angiotensin 1-7 axis of the renin-angiotensin system in heart failure. Circ Res 2016;118:1313-26.
- Vickers C, Hales P, Kaushik V, Dick L, Gavin J, Tang J, et al. Hydrolysis of biological peptides by human angiotensin-converting enzyme-related carboxypeptidase. J Biol Chem 2002;277:14838-43.
- Gheblawi M, Wang K, Viveiros A, Nguyen Q, Zhong JC, Turner AJ, et al. Angiotensin converting Enzyme 2: SARS-CoV-2 receptor and regulator of the renin-angiotensin system: celebrating the 20th anniversary of the discovery of ACE2. Circ Res 2020;126:1456-74.
- Yan R, Zhang Y, Li Y, Xia L, Guo Y, Zhou Q. Structural basis for the recognition of SARS-CoV-2 by full-length human ACE2. Science 2020;367:1444-8.
- Li W, Moore MJ, Vasilieva N, Sui J, Wong SK, Berne MA, et al. Angiotensin-converting enzyme 2 is a functional receptor for the SARS coronavirus. Nature 2003;426:450-4.
- Walls AC, Park YJ, Tortorici MA, Wall A, McGuire AT, Veesler D. Structure, function, and antigenicity of the SARS-CoV-2 spike glycoprotein. Cell 2020;181:281-92.e6.
- Fu J, Zhou B, Zhang L, Balaji KS, Wei C, Liu X, et al. Expressions and significances of the angiotensin-converting enzyme 2 gene, the receptor of SARS-CoV-2 for COVID-19. Mol Biol Rep 2020;47:4383-92.
- Chen Y, Guo Y, Pan Y, Zhao ZJ. Structure analysis of the receptor binding of 2019-nCoV. Biochem Biophys Res Commun 2020;525:135-40.
- Zhou P, Yang XL, Wang XG, Hu B, Zhang L, Zhang W, et al. A pneumonia outbreak associated with a new coronavirus of probable bat origin. Nature 2020;579:270-3.
- Qiu Y, Zhao YB, Wang Q, Li JY, Zhou ZJ, Liao CH, et al. Predicting the angiotensin converting enzyme 2 (ACE2) utilizing capability as the receptor of SARS-CoV-2. Microbes Infect 2020;22:221-5.
- Li W, Zhang C, Sui J, Kuhn JH, Moore MJ, Luo S, et al. Receptor and viral determinants of SARS-coronavirus adaptation to human ACE2. EMBO J 2005;24:1634-43.
- Wan Y, Shang J, Graham R, Baric RS, Li F. Receptor recognition by the novel coronavirus from Wuhan: an analysis based on decade-long structural studies of SARS coronavirus. J Virol 2020;94:e00127-20.
- Rice GI, Jones AL, Grant PJ, Carter AM, Turner AJ, Hooper NM. Circulating activities of angiotensin-converting enzyme, its homolog, angiotensin-converting enzyme 2, and neprilysin in a family study. Hypertension 2006;48:914-20.
- Ciaglia E, Vecchione C, Puca AA. COVID-19 infection and circulating ACE2 levels: protective role in women and children. Front Pediatr 2020;8:206.
- Hussain M, Jabeen N, Raza F, Shabbir S, Baig AA, Amanullah A, et al. Structural variations in human ACE2 may influence its binding with SARS-CoV-2 spike protein. J Med Virol :10.1002/jmv.25832.
- Xia S, Liu M, Wang C, Xu W, Lan Q, Feng S, et al. Inhibition of SARS-CoV-2 (previously 2019-nCoV) infection by a highly potent pan-coronavirus fusion inhibitor targeting its spike protein that harbors a high capacity to mediate membrane fusion. Cell Res 2020;30:343-55.
- Wang D, Hu B, Hu C, Zhu F, Liu X, Zhang J, et al. Clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus-infected pneumonia in Wuhan, China. JAMA 2020;323:1061-9.
- Guan WJ, Ni ZY, Hu Y, Liang WH, Ou CQ, He JX, et al. Clinical characteristics of coronavirus disease 2019 in China. N Engl J Med 2020;382:1708-20.
- Chen J, Jiang Q, Xia X, Liu K, Yu Z, Tao W, et al. Individual variation of the SARS-CoV-2 receptor ACE2 gene expression and regulation. Aging Cell 2020;19:e13168.
- Cao Y, Li L, Feng Z, Wan S, Huang P, Sun X, et al. Comparative genetic analysis of the novel coronavirus (2019-nCoV/SARS-CoV-2) receptor ACE2 in different populations. Cell Discov 2020;6:11.
- Zhao Y, Zhao Z, Wang Y, Zhou Y, Ma Y, Zuo W. Single-cell RNA expression profiling of ACE2, the receptor of SARS-CoV-2. Am J Respir Crit Care Med 2020;202:756-9.
- Li M, Li L, Zhang Y, Wang X. Expression of the SARS-CoV-2 cell receptor gene ACE2 in a wide variety of human tissues. Infect Dis Poverty 2020;9:45.
- Bénéteau-Burnat B, Baudin B, Morgant G, Baumann FC, Giboudeau J. Serum angiotensin-converting enzyme in healthy and sarcoidotic children: comparison with the reference interval for adults. Clin Chem 1990;36:344-6.
- Day CW, Baric R, Cai SX, Frieman M, Kumaki Y, Morrey JD, et al. A new mouse-adapted strain of SARS-CoV as a lethal model for evaluating antiviral agents in vitro and in vivo. Virology 2009;395:210-22.
- Ghadhanfar E, Alsalem A, Al-Kandari S, Naser J, Babiker F, Al-Bader M. The role of ACE2, angiotensin-(1-7) and Mas1 receptor axis in glucocorticoid-induced intrauterine growth restriction. Reprod Biol Endocrinol 2017;15:97.
- NCBI. TMPRSS2 transmembrane serine protease 2 [
Homo sapiens(human)]. https://www.ncbi.nlm.nih.gov/gene/7113 [Updated on 20 Sep 2020].
- Lucas JM, Heinlein C, Kim T, Hernandez SA, Malik MS, True LD, et al. The androgen-regulated protease TMPRSS2 activates a proteolytic cascade involving components of the tumor microenvironment and promotes prostate cancer metastasis. Cancer Discov 2014;4:1310-25.
- Hoffmann M, Kleine-Weber H, Schroeder S, Krüger N, Herrler T, Erichsen S, et al. SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor. Cell 2020;181:271-80.e8.
- Böttcher E, Matrosovich T, Beyerle M, Klenk HD, Garten W, Matrosovich M. Proteolytic activation of influenza viruses by serine proteases TMPRSS2 and HAT from human airway epithelium. J Virol 2006;80:9896-8.
- Shulla A, Heald-Sargent T, Subramanya G, Zhao J, Perlman S, Gallagher T. A. transmembrane serine protease is linked to the severe acute respiratory syndrome coronavirus receptor and activates virus entry. J Virol 2011;85:873-82.
- Watanabe R, Matsuyama S, Shirato K, Maejima M, Fukushi S, Morikawa S, et al. Entry from the cell surface of severe acute respiratory syndrome coronavirus with cleaved S protein as revealed by pseudotype virus bearing cleaved S protein. J Virol 2008;82:11985-91.
- Belouzard S, Chu VC, Whittaker GR. Activation of the SARS coronavirus spike protein via sequential proteolytic cleavage at two distinct sites. Proc Natl Acad Sci 2009;106:5871-6.
- Matsuyama S, Nagata N, Shirato K, Kawase M, Takeda M, Taguchi F. Efficient activation of the severe acute respiratory syndrome coronavirus spike protein by the transmembrane protease TMPRSS2. J Virol 2010;84:12658-64.
- Kam YW, Okumura Y, Kido H, Ng LFP, Bruzzone R, Altmeyer R. Cleavage of the SARS coronavirus spike glycoprotein by airway proteases enhances virus entry into human bronchial epithelial cells in vitro. PLoS One 2009;4:e7870.
- Heurich A, Hofmann-Winkler H, Gierer S, Liepold T, Jahn O, Pöhlmann S. TMPRSS2 and ADAM17 cleave ACE2 differentially and only proteolysis by TMPRSS2 augments entry driven by the severe acute respiratory syndrome coronavirus spike protein. J Virol 2014;88:1293-307.
- Asselta R, Paraboschi EM, Mantovani A, Duga S.
ACE2and TMPRSS2variants and expression as candidates to sex and country differences in COVID-19 severity in Italy. Aging (Albany NY) 2020;12:10087-98.
- FitzGerald LM, Agalliu I, Johnson K, Miller MA, Kwon EM, Hurtado-Coll A, et al. Association of
TMPRSS2-ERGgene fusion with clinical characteristics and outcomes: results from a population-based study of prostate cancer. BMC Cancer 2008;8:230.
- Clinckemalie L, Spans L, Dubois V, Laurent M, Helsen C, Joniau S, et al. Androgen regulation of the
TMPRSS2gene and the effect of a SNP in an androgen response element. Mol Endocrinol 2013;27:2028-40.
- Senapati S, Kumar S, Singh AK, Banerjee P, Bhagavatula S. Assessment of risk conferred by coding and regulatory variations of TMPRSS2 and CD26 in susceptibility to SARS-CoV-2 infection in human. J Genet 2020;99:53.
- Vankadari N, Wilce JA. Emerging WuHan (COVID-19) coronavirus: glycan shield and structure prediction of spike glycoprotein and its interaction with human CD26. Emerg Microbes Infect 2020;9:601-4.
- Beutler B. Innate immunity: an overview. Mol Immunol 2004;40:845-59.
- Ivashkiv LB, Donlin LT. Regulation of type I interferon responses. Nat Rev Immunol 2014;14:36-49.
- Schneider WM, Chevillotte MD, Rice CM. Interferon-stimulated genes: a complex web of host defenses. Annu Rev Immunol 2014;32:513-45.
- García-Sastre A, Biron CA. Type 1 interferons and the virus-host relationship: a lesson in détente. Science 2006;312:879-82.
- Stender JD, Glass CK. Epigenomic control of the innate immune response. Curr Opin Pharmacol 2013;13:582-7.
- Agalioti T, Lomvardas S, Parekh B, Yie J, Maniatis T, Thanos D. Ordered recruitment of chromatin modifying and general transcription factors to the IFN-β promoter. Cell 2000;103:667-78.
- Busslinger M, Tarakhovsky A. Epigenetic control of immunity. Cold Spring Harb Perspect Biol 2014;6:a019307.
- Smale ST, Tarakhovsky A, Natoli G. Chromatin contributions to the regulation of innate immunity. Annu Rev Immunol 2014;32:489-511.
- Marban C, Suzanne S, Dequiedt F, de Walque S, Redel L, Van Lint C, et al. Recruitment of chromatin-modifying enzymes by CTIP2 promotes HIV-1 transcriptional silencing. EMBO J 2007;26:412-23.
- Pinto BGG, Oliveira AER, Singh Y, Jimenez L, Gonçalves ANA, Ogava RLT, et al. ACE2 Expression is Increased in the Lungs of Patients with Comorbidities Associated with Severe COVID-19. J Infect Dis 2020;222:556-63.
- Sawalha AH, Zhao M, Coit P, Lu Q. Epigenetic dysregulation of ACE2 and interferonregulated genes might suggest increased COVID-19 susceptibility and severity in lupus patients. Clin Immunol 2020;215:108410.
- Pfeffer S, Zavolan M, Grässer FA, Chien M, Russo JJ, Ju J, et al. Identification of virus-encoded microRNAs. Science 2004;304:734-6.
- Saçar Demirci MD, Adan A. Computational analysis of microRNA-mediated interactions in SARS-CoV-2 infection. PeerJ 2020;8:e9369.