SARS-CoV-2 spike D614G variant exhibits enhanced replication and transmissibility

Nearly 11 months into the coronavirus disease (COVID-19) pandemic, scientists have unveiled much information about the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The virus, which has infected over 46 million people, has evolved, and the D614G substitution in the spike (S) protein emerged.  This mutation is now the predominant circulating variant (S-614G) of the pandemic.

A team of scientists from Switzerland, Germany, and the USA has demonstrated that the S-614G variant has enhanced binding to human angiotensin-converting enzyme 2 (ACE2), the cellular gateway of SARS-CoV-2. The variant also showed enhanced replication and transmissibility in animal models. p

COVID-19 pandemic

It has been nearly a year since the SARS-CoV-2 infection emerged in Wuhan City, China, in late December 2019. The viral infection rapidly developed into the coronavirus pandemic, which has affected 190 countries and territories worldwide.

The total global case toll has now topped 46.83 million, and the virus has claimed over 1.2 million lives. Though most of the cases experienced mild to moderate symptoms, a small fraction had severe illness. The infection may cause severe symptoms in people who are at high-risk, including the elderly, those with underlying health conditions, and those with weakened immune systems.

The entry of the SARS-CoV-2 into cells is dependent on the interaction of the spike glycoprotein (S) and the host cell surface receptor angiotensin-converting enzyme 2 (ACE2). During the virus's entry into the cell, the receptor-binding domain (RBD) within the S1 subunit connects to the ACE2, forming changes in the S2 subunit.

The S-D614G is a protein variant that contains a substitution in the S protein outside of the RBD. It is thought to weaken the S protein trimer's interprotomer latch between the S1 and S2 domains. Hence, this improves ACE2 binding and enhances the chance of infection.

As the pandemic evolved, the SARS-CoV-2 S-614G variant has rapidly surpassed the parental S-614D variant. Today, the S-614G variant has become dominant.

The study

To determine the S-D614 substitution role in the spread and predominance of this variant amid the COVID-19 pandemic, the team described the S protein binding to the human ACE2 and replication in vitro. Further, the team assessed infection and transmission dynamics in vivo using animal models – mice, Syrian hamsters, and ferrets.

The team used the biolayer interferometry (BLI) technology to determine if S-G614G substitution affects the binding between the spike protein and the ACE2. The method aims to quantify the binding affinity of the two.

In the study, published as a preprint on the bioRxiv* server, the researchers found functional changes by the D614G substitution in the S protein, which showed increased infection. Also, the team revealed that the variant exhibits increased replication and transmission.

However, the team noted that there is no evidence for a phenotypic change in the pathogenicity of the animal models, which means that infection with the SARS-CoV-2 S-614G variant is not linked to the development of severe COVID-19 in humans.

Further, the researchers said that the pandemic will still give rise to additional variants of the virus, which may display phenotypic changes and adaptations to humans. It is crucial to immediately track the genetic variability of emerging variants using whole-genome sequencing, assessing the virus phenotypes, and reconstructing the emerging virus variants, in order to implement a rapid response to mitigate the spread of the virus.

“Collectively, our data show that while the S-614G substitution results in subtle increases in binding and replication in vitro, it provides a real competitive advantage in vivo, particularly during the transmission bottleneck, providing an explanation for the global predominance of S-614G variant among the SARS-CoV-2 viruses currently circulating,” the researchers concluded in the study.

With the emerging data about COVID-19, scientists are getting near to finding therapies, treatments, and potential vaccines against the coronavirus. While there are still no treatments available, health agencies urged the pubic to perform mitigation strategies to prevent infection, including washing the hands regularly, wearing face masks, and observing social distancing.

*Important Notice

bioRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.

Journal reference:
Angela Betsaida B. Laguipo

Written by

Angela Betsaida B. Laguipo

Angela is a nurse by profession and a writer by heart. She graduated with honors (Cum Laude) for her Bachelor of Nursing degree at the University of Baguio, Philippines. She is currently completing her Master's Degree where she specialized in Maternal and Child Nursing and worked as a clinical instructor and educator in the School of Nursing at the University of Baguio.


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