Virus News: Korean Scientist Discover New SARS-CoV-2 Mutations That May Explain High Pathogenicity Of COVID-19 And Warn Of Effects On Vaccines
Korean Scientist from Konkuk University-Seoul, Yeungnam University-Daegu, Inje University-Seoul, Seoul National University and also experts from University of Colorado Denver-USA have discovered new mutations on the SARS-CoV-2 genome from samples taken from infected Korean COVID-19 patients. The researchers warn that these new mutations can have critical implications on the current COVID-19 vaccines programmes underway.
SARS-CoV-2is a positive-sense single-stranded RNA (+ssRNA) that causes COVID-19. The viral genome encodes twelve genes for viral replication and infection. The third open reading frame is the spike (S) gene that encodes for the spike glycoprotein interacting with specific cell surface receptor angiotensin converting enzyme 2 (ACE2) on the host cell membrane. Most recent studies identified a single point mutation in S gene. A single point mutation in S gene leading to an amino acid substitution at codon 614 from an aspartic acid 614 into glycine (D614G) resulted in greater infectivity compared to the wild type SARS-CoV2.
The study team was interested in investigating the mutation region of S gene of SARS-CoV2 from Korean COVID-19 patients. Alarmingly new mutation sites were found in the critical receptor binding domain (RBD) of S gene, which is adjacent to the aforementioned D614G mutation residue. While it is interesting that the D614G mutation exists in all four Korean COVID-19 patients in the study, the study team found two additional mutations G504D/V524D within the critical RBD domain of S gene. A third P579L mutation is located near the known D614G mutation in SD2 but without known specific function.
The team said that it was necessary to investigate the function of different domains in spike gene to explain the significance of the mutations in SARS-CoV2 pathogenicity.
This specific sequence data demonstrated the active progression of SARS-CoV2 by mutations in the RBD of S gene. The sequence information of new mutations is critical to the development of recombinant SARS-CoV2 spike antigens, which may be required to improve and advance the vaccine and therapeutic strategy against a wide range of possible SARS-CoV2 mutations.
The study findings were published in the peer-reviewed journal: Immune Network. https://immunenetwork.org/DOIx.php?id=10.4110/in.2020.20.e41
The study team has identified these novel genetic variants that demonstrate the active mutational progression of SARS-CoV-2, the agent that causes COVID-19.
Importantly two of the mutations occurred in the receptor-binding domain of the viral spike protein ie the structure the virus uses to bind to host cells and this could have implications for vaccines and antibody protocols.
Interestingly a third mutation occurred in a subdomain of the spike protein, close to the well-established D614G variant that is known to have enhanced the infectivity and spread of the virus. The SARS-CoV-2 spike D614G variant has been the dominant strain globally since the end of March.
Corresponding author Professor Dr Soohyun Kim Laboratory of Cytokine Immunology, Department of Bi
omedical Science and Technology, Konkuk University told Thailand Medical News, "This specific sequence data demonstrated the active progression of SARS-CoV-2 by mutations in the RBD of S (spike]) gene. The present study with novel mutations in critical RBD of S gene may explain the high pathogenicity of SARS-CoV-2."
The study team says the sequence information for such novel mutations is essential for the development of recombinant SARS-CoV-2 spike antigens that could help to advance strategies against the potentially wide range of mutations that could emerge.
The SARS-CoV-2 virus is one of seven coronaviruses that infect humans, including the betacoronaviruses SARS-CoV-1 and Middle East respiratory syndrome coronavirus (MERS-CoV) that led to outbreaks in 2002-2003 and 2012, respectively. SARS-CoV-2 is however particularly infectious and has caused unprecedented medical, social, and economic destruction across many parts of the globe.
Significantly the S gene of SARS-CoV-2 encodes a surface structure on the viral envelope called the spike glycoprotein. The spike protein is cleaved by host cell protease into two domains, namely the S1 and S2 subunits.
Importantly the S1 subunit contains the receptor-binding domain (RBD) that recognizes and interacts with the host cell receptor angiotensin-converting enzyme 2. This is followed by conformational changes in the S2 subunit that allow membrane fusion and delivery of the viral genome into the cell.
Dr Kim added, "Elucidating more precisely how SARS-CoV-2 enters host cells is a priority as disruption of this entry can mitigate the replication and spread of SARS-CoV2.”
Past research has identified that a single point mutation (D614G) in the S gene has resulted in enhanced infectivity of SARS-CoV-2, compared with the wildtype virus. However, the significance of this new mutation is uncertain, since it is located in the S2 subunit rather than the RBD, say Dr Kim and colleagues.
Although the SARS-CoV-2 genome shares around 80% identity with the genome of SARS-CoV-1, which also uses ACE2 to enter target cells, SARS-CoV-2 is far more infectious and transmissible than SARS-CoV-1, despite similar a genome sequence and shared host cell receptor.
Another study comparing the cleavage site of SARS-CoV-1 and SARS-CoV-2 found a difference in the cleavage of the S1 and S2 subunits, which Dr Kim and colleagues say may account for the difference in infectivity.
In the study, nasopharyngeal swabs taken from Korean patients with COVID-19 were tested for SARS-CoV-2 infection. Four positive samples were used to isolate the S gene and investigate the RBD of spike.
The N-terminal region of the S gene was translated into an amino acid sequence, which was entered into the (National Center for Biotechnology Information) NCBI database. This revealed two novel mutations (G504D/V524D) within the critical RBD of the S gene.
Furthermore a third mutation (P579L) was identified in subdomain 2, close to the D614G mutation, but without any known specific function, say the researchers.
Dr Kim added, "Therefore, it is necessary to investigate the function of different domains in spike gene to explain the significance of the mutations in SARS-CoV2 pathogenicity.”
Dr Kim and colleagues say these novel mutations in the critical RBD of the S gene demonstrate the progression of SARS-CoV-2 in Korean COVID-19 patients.
The study team concludes, "The sequence information of new mutations is critical to the development of recombinant SARS-CoV2 spike antigens, which may be required to improve and advance the strategy against a wide range of possible SARS-CoV-2 mutations.”
It should be noted that it is the spike proteins that are being used in most of the RNA based vaccines that are under development and such emerging mutations in the S proteins or RBD regions could have massive implications on the effectiveness of these vaccines. More urgent research is warranted the study team also warned.
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