Researchers in Korea and the United States have identified novel genetic variants that demonstrate the active mutational progression of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) – the agent that causes coronavirus disease 2019 (COVID-19).
Two of the mutations occurred in the receptor-binding domain of the viral spike protein – the structure the virus uses to bind to host cells.
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.
"This specific sequence data demonstrated the active progression of SARS-CoV-2 by mutations in the RBD of S [spike] gene," writes the team. "The present study with novel mutations in critical RBD of S gene may explain the high pathogenicity of SARS-CoV-2."
The researchers say 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 study, recently published in the journal Immune Networks, was conducted by Soohyun Kim and colleagues at Konkuk University along with collaborators from various other institutions in Korea and from the University of Colorado and National Jewish Health in Denver, USA.
Seven coronaviruses infect humans
SARS-CoV-2 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.
However, SARS-CoV-2 is particularly infectious and has caused unprecedented medical, social, and economic destruction across many parts of the globe.
"The current SARS-CoV-2 is highly contagious and has caused the worst pandemic on earth in the past 100 years," say Kim and colleagues.
The importance of the S gene and spike protein
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.
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.
"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," writes the team.
Studies have 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 mutation is uncertain, since it is located in the S2 subunit rather than the RBD, say Kim and colleagues.
The SARS-CoV-2 genome shares around 80% identity with the genome of SARS-CoV-1, which also uses ACE2 to enter target cells.
Yet, SARS-CoV-2 is far more infectious and transmissible than SARS-CoV-1, despite similar a genome sequence and shared host cell receptor.
A recent 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 Kim and colleagues say may account for the difference in infectivity.
What did the current study find?
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.
A third mutation (P579L) was identified in subdomain 2, close to the D614G mutation, but without any known specific function, say the researchers.
"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," they write.
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 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," concludes the team.
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