In December 2019, a distinctive coronavirus (CoV) was determined to be responsible for an outbreak of potentially fatal atypical pneumonia, ultimately defined as coronavirus disease 19 (COVID-19), in Wuhan, Hubei province, China. This novel CoV, termed severe acute respiratory syndrome (SARS)-CoV-2, was found to be similar to the CoV that was responsible for the SARS pandemic that occurred in 2002.
What Is Coronavirus?
CoVs are a large family of enveloped, positive-sense, single-stranded RNA viruses that infect a broad range of vertebrates. They are extensive in bats but can be found in many other birds and mammals including humans. CoVs can cause a variety of diseases such as enteritis in pigs and cows and upper respiratory disease in chickens.1 In humans, CoVs tend to cause mild to moderate upper respiratory tract infections such as the common cold.2,3 However, in the past couple of decades, there have been outbreaks of severe, and sometimes fatal, respiratory illnesses that were later found to be caused by novel, human pathogenic CoVs. These CoV strains, which were determined to be phylogenetically distinct from the common human CoVs, had originated in bats and were transmitted to humans, typically through an intermediate host.1,4,5 These strains exhibited stronger virulence and quickly passed from human to human. While infection with these CoVs typically produced mild symptoms, for certain individuals, responses were more severe. In extreme cases, death occurred due to gradual respiratory failure as the result of alveolar damage.3,4,6
|Figure 1. ACE-2 is the host cell receptor responsible for mediating infection by SARS-CoV-2, the novel coronavirus responsible for coronavirus disease 2019 (COVID-19). Treatment with anti-ACE-2 antibodies disrupts the interaction between virus and receptor.
Comparing the SARS and COVID-19 Pandemics
The SARS pandemic that occurred in 2002 originated in the Guangdong Province in southern China. According to the World Health Organization (WHO), the CoV responsible for this disease, SARS-CoV, spread rapidly through 29 countries in Southeast Asia where it resulted in 8096 confirmed cases of SARS, with 774 of these individuals dying.7,8 Today’s pandemic has surpassed these numbers. The WHO has estimated that to date, over 110,000 individuals in over 100 countries have been diagnosed with COVID-19, with over 4,000 of these individuals dying.9 The rapid spread of this respiratory illness has resulted in a coordinated international effort to quickly characterize the etiology agent in order to develop potential vaccines and/or therapeutic agents that specifically target the virus or host cell components necessary for viral replication.
Identification and Characterization of SARS-CoV-2
Identification and sequencing of the virus responsible for COVID-19 (view SARS-CoV-2 protein sequence) determined that it was a novel CoV that shared 88% sequence identity with two bat-derived SARS-like CoV, suggesting it had originated in bats.10 Additionally, it was shown that this CoV, which was termed 2019-nCoV or SARS-CoV-2, shared 79.5% sequence identity with SARS-CoV.5,10 The coronaviral genome encodes four major structural proteins: the spike (S) protein, nucleocapsid (N) protein, membrane (M) protein, and the envelope (E) protein.6 The S protein is responsible for facilitating entry of the CoV into the target cell. It is composed of a short intracellular tail, a transmembrane anchor, and a large ectodomain that consists of a receptor binding S1 subunit and a membrane-fusing S2 subunit.11 Sequence analysis of the SARS-CoV-2 S protein genome showed that it was only 75% identical with the SARS-CoV S protein.5,10 However, analysis of the receptor binding motif (RBM) in the S protein showed that most of the amino acid residues essential for receptor binding were conserved between SARS-CoV and SARS-CoV-2, suggesting that the 2 CoV strains use the same host receptor for cell entry.12 The entry receptor utilized by SARS-CoV is Angiotensin-Converting Enzyme 2 (ACE-2).13
ACE-2 is a type I transmembrane metallocarboxypeptidase with homology to ACE, an enzyme long-known to be a key player in the Renin-Angiotensin system (RAS) and a target for the treatment of hypertension.14 It is mainly expressed in vascular endothelial cells, the renal tubular epithelium, and in Leydig cells in the testes.15,16 PCR analysis revealed that ACE-2 is also expressed in the lung, kidney, and gastrointestinal tract, tissues shown to harbor SARS-CoV.17-19 The major substrate for ACE-2 is Angiotensin II.20 ACE-2 degrades Angiotensin II to generate Angiotensin 1-7, thereby, negatively regulating RAS.15,20 ACE-2 has also been shown to exhibit a protective function in the cardiovascular system and other organs.15
ACE-2 is an Entry Receptor for SARS-CoV-2
Based on the sequence similarities of the RBM between SARS-CoV-2 and SARS-CoV, several independent research groups investigated if SARS-CoV-2 also utilizes ACE-2 as a cellular entry receptor. Zhou et al. showed that SARS-CoV-2 could use ACE-2 from humans, Chinese horseshoe bats, civet cats, and pigs to gain entry into ACE-2-expressing HeLa cells.5 Hoffmann et al. reported similar findings for human and bat ACE-2.21 Additionally, Hoffmann et al. showed that treating Vero-E6 cells, a monkey kidney cell line known to permit SARS-CoV replication, with an Anti-ACE-2 Antibody (R&D Systems, Catalog # AF933) blocked entry of VSV pseudotypes expressing the SARS-CoV-2 S protein.21
Inhibiting TMPRSS2 Activity Blocks SARS-CoV-2 Entry
For SARS-CoV entry into a host cell, its S protein needs to be cleaved by cellular proteases at 2 sites, termed S protein priming, so the viral and cellular membranes can fuse.22 Specifically, S protein priming by the serine protease TMPRSS2 is crucial for SARS-CoV infection of target cells and spread throughout the host.23,24 Hoffmann et al. investigated if SARS-CoV-2 entry is also dependent on S protein priming by TMPRSS2. Treatment of the Calu-3 human lung cell line with the serine protease inhibitor camostat mesylate partially blocked entry of VSV pseudotypes expressing the SARS-CoV-2 S protein.21 Similar effects of camostat mesylate treatment were seen with primary human lung cells and with Calu-3 cells incubated with authentic SARS-CoV-2.21
Avenues for COVID-19 Therapies
These new findings could greatly impact the development of effective therapies for COVID-19. For instance, anti-ACE-2 antibodies could be used to block SARS-CoV-2 binding to the receptor. Additionally, TMPRSS2 inhibitors could be used to prevent SARS-CoV-2 entry into host cells. Camostat has been used to treat chronic pancreatitis in Japan and is currently undergoing Phase 1/2 trial testing in the United States.26 If deemed safe, camostat could be a potential treatment option of CoV infections.27 It is also possible that antibodies developed during SARS-CoV infection could help prevent or treat COVID-19. Hoffmann et al. showed that sera from recovering SARS patients reduced SARS-CoV-2 S protein-driven entry into Vero-E6 cells.21 However, future studies are needed to determine whether any of these options are effective in disrupting the interaction between virus and receptor in vivo.
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