Researchers from the University of Texas in the United States genetically engineered the SARS-CoV-2 strain USA-WA1/2020 to carry the D614G mutation and described its effects.
The novel coronavirus SARS-CoV-2 causes coronavirus disease in 2019 (COVID-19) and is now rampant worldwide. Vaccines are an essential countermeasure urgently needed to control a pandemic. There is no human vaccine against SARS-CoV-2, but approximately 120 vaccine candidates are under development.
SARS-CoV-2 and two other closely related highly pathogenic viruses, SARS-CoV and MERS-CoV, belong to the genus Betacoronavirus in the family Coronaviridae. SARS-CoV-2 has a sense, single-stranded RNA genome of 30 kb in size. Its nucleocapsid protein (N) and outer membrane composed of membrane protein (M), envelope protein (E), and spike protein (S) coat its genome.
Like SARS-CoV, the S protein of SARS-CoV-2 binds to their common receptor, angiotensin-converting enzyme 2 (ACE2), via a receptor-binding domain (RBD), mediating viral entry into host cells. Prior to this, scientists have confirmed that the RBDs of SARS-CoV and MERS-CoV contain major conformation-dependent neutralizing epitopes and are able to elicit potent neutralizing antibodies in immunized animals, so they are promising vaccine development targets.
In July 2020, researchers from the Duke University Human Vaccine Institute, Los Alamos National Laboratory, La Jolla Institute of Immunology, the University of Washington, Harvard University, and the University of Sheffield, UK, found that the SARS-CoV-2 spike protein (S protein) mutation D614G improved the ability of this virus to infect human cells and helped it become the dominant strain spreading in the world today (Cell, 2020, Fig. doi:10.1016/j.cell .2020.06.043). This SARS-CoV-2 carrying the D614G mutation (Hereafter referred to as D614G variant, or D614G virus variant) rapidly becomes the dominant strain shortly after its first appearance. However, the impact of this mutation on virus transmission and vaccine efficacy remains to be determined.
In September 2020, researchers from the University of Massachusetts Medical School, Harvard University, Thermo Fisher Scientific, and Regeneron Pharmaceuticals in the United States found that the D614G variant was more infectious than its ancestral virus on human pneumocytes, colonocytes, and cells that were allowed to be infected by this virus by ectopic expression of human ACE2 or ACE2 homologs from various mammals (including Chinese chrysanthemum and Malayan pangolin) (Cell, 2020, Fig. doi:10.1016/j.cell .2020.09.032). Evaluation of the S protein trimer by cryo-electron microscopy showed that D614G disrupts the contact between the protomer of the S protein and shifts the conformation of the S protein to a state that is able to bind ACE2, which is thought to be a pathway for the fusion of viral particles with target cell membranes. Consistent with this more open conformation, the neutralizing potency of antibodies targeting the receptor binding domain (RBD) of the S protein was not diminished.
Today, in a new study, researchers from the University of Texas in the United States genetically engineered the SARS-CoV-2 strain USA-WA1/2020 to carry the D614G mutation and described its effects. They found that D614G enhanced replication in human lung epithelial cells and primary human airway tissue by increasing the infectivity of this strain. The relevant findings were recently published in Nature, and the paper was entitled "Spike mutation D614G alters SARS-CoV-2 fitness".
Hamsters infected with the G614 variant produce higher infectious virus in nasal washes and trachea rather than in the lungs, which confirms previous clinical evidence that the D614G mutation increases viral load in the upper respiratory tract of COVID-19 patients and may increase transmission.
Sera from hamsters infected with the D614 variant neutralized G614 variants modestly more than D614 variants, suggesting that (i) this mutation may not diminish the ability of the vaccine to protect against COVID-19 in clinical trials and (ii) therapeutic antibody testing should be performed against transmitted G614 variants. Combined with clinical findings, this study highlights the importance of this mutation in virus transmission, vaccine efficacy, and antibody therapy.
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