Back in December 2019, a distinguishing coronavirus (CoV) has been determined to be in charge of an epidemic of potentially deadly atypical pneumonia, finally defined as coronavirus disorder 19 (SARS-CoV-2), in Wuhan, Hubei province, China. This novel CoV, termed severe acute respiratory syndrome (SARS)-CoV-2, was shown to be like this CoV that was at fault to the SARS pandemic which happened in 2002.
What Is this coronavirus?
Coronaviruses are a large family of enveloped, positive-sense, single-stranded RNA viruses that infect a broad range of animals.
They can be extensive in bats but can be located in a number of different animals, like Aves and mammas, causing upper respiratory disease. There are cases of pigs, cows, chickens, and even humans. Normally, the virus causes mild to moderate upper respiratory tract ailments like the frequent cold. Nonetheless, in the last few decades, there were outbreaks of acute, and sometimes deadly, respiratory disorders which were later proven to result from publication, individual pathogenic CoVs. All these CoV strains, which have been decided to be phylogenetically different from the typical individual CoVs, had originated from bats and were sent to people, normally via an intermediate host. These strains demonstrated stronger virulence and passed from human to human. While disease using these CoVs typically generated mild symptoms, for some people, responses were significantly more acute. In extreme cases, death occurred because of slow respiratory failure as caused by alveolar damage.
Comparing the the last big coronavirus pandemics: SARS and SARS-CoV-2
The SARS pandemic Which Happened in 2002 originated from the Guangdong, China. According to the World Health Organization (WHO), the CoV accountable for this disorder, SARS-CoV, propagate quickly through 29 nations in Southeast Asia in which it led in 8096 confirmed cases of SARS, with 774 of those individuals facing a fatal end. The current pandemic has been even more severe. The WHO has estimated the date, over 208,000 people in over 100 nations are diagnosed with SARS-CoV-2, with over 8,000 of those people reached their ending. The fast spread of the respiratory disease has caused a coordinated global effort to rapidly describe the etiology agent so as to develop potential vaccines or therapeutic agents that specifically target the virus or host cell elements necessary for viral replication.
Are there any structural differences between the two viruses?
Identification and sequencing of the virus in charge of SARS-CoV-2 decided it was a book CoV that shared 88% sequence identity with two bat-derived SARS-like CoV, implying it had originated from these mammals. It also was revealed that this CoV, that was named 2019-nCoV, SARS-CoV-2 or COVID-2019, shared 79.5% sequence identity with SARS-CoV. The coronavirus genome contains four major structural components:
- the spike (S) protein,
- nucleocapsid (N) protein,
- membrane (M) protein,
- and the envelope (E) protein
The S protein is responsible for facilitating entry of their CoV to the target cell. It’s made up of a short intracellular tail, a transmembrane anchor, and also a large ectodomain which is made up of receptor binding S1 subunit and a membrane-fusing S2 subunit. Sequence analysis of this COVID-2019 S protein genome revealed it was just 75% identical with the SARS-CoV S T protein. Nevertheless, analysis of this receptor binding motif (RBM) from the S protein revealed that the majority of the amino acid residues essential for receptor binding were stored between SARS-CoV and COVID-2019, indicating the 2-CoV strains utilize the identical host receptor for cell entry.
What is ACE-2?
ACE-2 is a type I transmembrane metallocarboxypeptidase using homology to ACE, a molecule long-known for an integral participant in the Renin-Angiotensin system (RAS) and also a goal for treating hypertension. It’s largely expressed in vascular endothelial cells, the renal tubular epithelium, and in Leydig cells in the testes. PCR analysis demonstrated that ACE-2 can also be expressed in the kidney, lung, and gastrointestinal tract, cells shown to haven SARS-CoV. The significant substrate for ACE-2 is Angiotensin II. ACE-2 degrades Angiotensin II to create Angiotensin 1-7, thereby, negatively modulating RAS. ACE-2 has additionally been demonstrated to show a protective role in the cardiovascular system and other organs.
ACE-2: an Entry Receptor for COVID-2019
Depending on the sequence similarities of the RBM involving COVID-2019 and SARS-CoV, many independent research teams researched if COVID-2019 also uses ACE-2 as a mobile entry receptor. Zhou et al. revealed that COVID-2019 may use ACE-2 from people, Chinese horseshoe pubs, civet cats, and pigs to get entrance to ACE-2-expressing HeLa cells. Hoffmann et al. reported comparable findings for bat and human ACE-2. Furthermore, Hoffmann et al. revealed that treating Vero-E6 cells, a monkey kidney cell line known to allow SARS-CoV replication, having an Anti-ACE-2 Antibody obstructed entrance of VSV pseudotypes expressing the COVID-2019 S protein.
Inhibiting TMPRSS2 Activity could actually Block COVID-2019 Entry?
To get SARS-CoV entry into a host cell, its S protein has to be cleaved by cellular proteases at two sites, termed S protein priming, therefore the viral and cellular membranes may fuse. Especially, S protein priming from the serine protease TMPRSS2 is essential to get SARS-CoV infection of target cells and spread through the bunch. Hoffmann et al. researched if COVID-2019 entrance is also determined by S protein priming by TMPRSS2. Remedy of this Calu-3 human lung cell line together with the serine protease inhibitor camostat mesylate partly blocked entrance of VSV pseudotypes expressing the COVID-2019 S T protein. Much like camostat mesylate therapy were observed with primary human lung tissues and also Calu-3 cells incubated with genuine COVID-2019.
These new findings may greatly affect the development of effective treatments for SARS-CoV-2. For example, anti-ACE-2 antibodies or may be used to stop COVID-2019 from binding to the receptor. Camostat was used as a treatment for chronic pancreatitis in Japan and is now undergoing Phase 1/2 trial tests at the USA. If the trials prove to be secure, camostat might be a possible treatment alternative of CoV infections. It’s also possible that antibodies developed through SARS-CoV disease might help prevent or cure SARS-CoV-2. Hoffmann et al. revealed that sera from recovering SARS patients decreased COVID-2019 S protein-driven entrance into Vero-E6 cells. That is why China broght sera with the other medical equipment to Italy, as for now, it is the worst affected country after China. However, future studies are required to ascertain if one of these options are successful in preventing the interaction between receptor and virus in vivo.