Novel mutations in SARS-CoV-2 may explain the high pathogenicity of COVID-19

Researchers in Korea and the United States have identified new genetic variants that demonstrate 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 used by the virus to bind to host cells.

A third mutation occurred in a subdomain of the spike protein, close to the well-established D614G variant which is known to have improved infectivity and spread of the virus. The SARS-CoV-2 spike D614G variant has been the dominant variety globally since late March.

“These sequence specific data demonstrated the active progression of SARS-CoV-2 by mutations in the RBD of S [spike] “, writes the team.” The present study with novel mutations in the critical RBD of the S gene may explain the high pathogenicity of SARS-CoV-2 “.

The researchers say sequence information for these new mutations is essential for the development of recombinant SARS-CoV-2 spike antigens that could help advance strategies against the potentially wide range of mutations that could emerge.

The study, recently published in the journal Immune networks, was led by Soohyun Kim and colleagues at Konkuk University along with collaborators from various other institutions in Korea and 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 SARS-CoV-1 betacoronaviruses and Middle East Respiratory Syndrome (MERS-CoV) coronavirus that led to outbreaks in 2002-2003 and 2012. , respectively.

However, SARS-CoV-2 is particularly contagious and has caused unprecedented medical, social and economic destruction in 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 the spike protein

The SARS-CoV-2 S gene encodes a surface structure on the viral envelope called a spike glycoprotein. The spike protein is cleaved by the host cell protease into two domains, namely the S1 and S2 subunits.

The S1 subunit contains the receptor binding domain (RBD) which recognizes and interacts with the host cell receptor 2 angiotensin converting enzyme. This is followed by conformational changes in the S2 subunit that allow for membrane fusion and the release of the viral genome into the cell.

‘Clarifying more precisely how SARS-CoV-2 enters host cells is a priority as disrupting this rumor can mitigate the replication and spread of SARS-CoV2, the team writes.

The studies identified that a single point mutation (D614G) in the S gene resulted in greater infectivity of SARS-CoV-2, compared to the wild-type virus. However, the significance of this mutation is uncertain, as it is found in the S2 subunit rather than the RBD, Kim and colleagues say.

The SARS-CoV-2 genome shares about 80% identity with the SARS-CoV-1 genome, which also uses ACE2 to enter target cells.

However, SARS-CoV-2 is much more infectious and transmissible than SARS-CoV-1, despite a similar genomic 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 said could explain the difference in infectivity.

What did the current study find?

Nasopharyngeal swabs taken from Korean COVID-19 patients were tested for SARS-CoV-2 infection. Four positive samples were used to isolate the S gene and study the spike RBD.

The N-terminal region of the S gene was translated into an amino acid sequence, which was entered in the NCBI (National Center for Biotechnology Information) database.

This revealed two new 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 with no known specific function, the researchers say.

“Therefore, it is necessary to study the function of different domains in the spike gene to explain the significance of the mutations in the pathogenicity of SARS-CoV2,” they write.

Kim and colleagues state that these new mutations in the critical RBD of the S gene demonstrate the progression of SARS-CoV-2 in Korean COVID-19 patients.

‘Sequence information for new mutations is critical for the development of recombinant SARS-CoV2 spike antigens, which may be needed to enhance and advance strategy against a wide range of possible SARS-CoV-2 mutations,’ the team concludes.