Why Is the SARS-CoV-2 Delta Strain So Contagious?

Chinese & English: Siddharth Sinha, Benjamin Tam, San Ming Wang‧Photo: Editorial Board, with some provided by the authors

The COVID-19 pandemic has had a devastating impact on global public health since late 2019. As of January 2022, the SARS-CoV-2 virus, which causes a symptom of pneumonia, has infected over 318 million, and killed over 5.5 million people. SARS-CoV-2 infects human cells through the ‘receptor-binding domain’ (RBD) on its spike (S) protein to the ‘angiotensin-converting enzyme 2’ (ACE2) receptor on the human cell surface. Therefore, RBD is a key determinant of SARS-CoV-2 infection in humans. SARS-CoV-2 is rapidly evolving, with new mutations constantly generated across its genome, including the RBD.

Analysis with Supercomputing Cluster in UM

While most mutations did not survive evolutionary selection, some of them provide a survival advantage for the virus. This is the case for the variant strains with mutations of L452R, T478K, E484K, E484Q, and N501Y in the RBD domain, which have caused several outbreaks due to the increased infectiousness of SARS-CoV-2 with these RBD mutations. Later, several new SARS-CoV-2 strains with RBD ‘double mutations’ began to emerge. These strains contain two of the single mutations mentioned above. They are more contagious than the strains with a single RBD mutation and have caused multiple outbreaks worldwide that have been more severe than those caused by the strains with a single mutation, putting unvaccinated populations in particular at high risk. Take the example of the Delta strain, which was first identified in India in October 2020. The strain contains a double RBD mutation L452R/T478K and is much more contagious than previous mutant strains in terms of severity of infections and hospitalisation rates. The Delta strain spread rapidly throughout the world and became the predominant strain of SARS-CoV-2.

To control the SARS-CoV-2 pandemic and develop better treatments, there is an urgent need to uncover the mechanism of increased transmissibility due to RBD mutations. It is suspected that the increased transmissibility of SARS-CoV-2 caused by RBD mutations may be related to the mutations causing stronger binding of the viral RBD to the human ACE2 receptor. However, clear evidence for this assumption is lacking. In our study, we investigated whether an increased RBD mutation could cause a structural change leading to a tighter binding between RBD and the human ACE2 receptor. We compared the effects of single mutations in RBD, including L452R, T478K, E484K, E484Q, and N501Y, with double mutations, including L452R/T478K (Delta), L452R/E484Q (Kappa), and E484K/N501Y (Beta, Gamma) on the relationship between RBD and ACE2 receptors, using the wild type as a control. Using the supercomputing cluster in UM’s Information and Communication Technology Office, we analysed single and double RBD mutations by using molecular dynamics simulations to measure the thermodynamic changes in the structure of the RBD mutants. We also visualised the mutation-induced changes in the RBD structure with superimposed structural comparisons, investigated the changes in free binding energy to determine the effect of mutations on the protein affinity between RBD and the ACE2 receptor, and tested the mutation-induced changes in the RBD surface structure and the neutralizing antibody binding sites.

This figure shows that mutated RBD decreases an antibody’s binding capacity. The antibody sites in the RBD are highlighted in different colours. Green: Native RBD; light blue: RBD single mutant E484K; magenta: RBD double mutant L452R/T478K; yellow: RBD double mutant L452R/E484Q; blue: RBD double mutant E484K/N501Y.

Research Results Included in WHO COVID-19 Guidelines

The results of our research show that double mutations have altered the structure of RBD in ways very different from those by single mutations: Double mutations have increased the binding strength between the RBD and the ACE2 receptor, altered antibody binding sites on the RBD, and reduced the effectiveness of neutralising antibody. Therefore, RBD double mutations directly contribute to the increased contagiousness of SARS-CoV-2 to the host cells through their increased binding to the ACE2 receptor. Our study was quickly accepted and published by the scientific journal Viruses (https://doi.org/10.3390/v14010001). It was also immediately cited by the World Health Organization in its ‘Living guidance for Clinical Management of COVID-19’ (https://www.who.int/publications/i/item/WHO-2019-nCoV-clinical-2021-2), published in 2021, to explain the high infectivity of RBD double mutations.

Prof San Ming Wang (right) specialises in cancer genetics and prevention

Omicron Mutant Strain

The Omicron mutant strain, discovered in South Africa, has recently replaced the Delta variant as the dominant strain in most parts of the world. There are 18 RBD mutations in Omicron, four of which (L452R, Y478K, E484K, N501Y) are the same as in the single and double mutant strains. Similar to the increased contagiousness from single mutations to double mutations, the combination of four RBD double mutations with the 14 new RBD mutations in Omicron is likely to cause a further increased contagiousness of SARS-CoV-2. The latest Deltacron variant, which is a hybrid between the Delta mutant and the Omicron mutant, suggests that the RBD mutation may continue to play important roles in the contagiousness of the new SARS-CoV-2 variants. The results of our study on single and double RBD mutations have direct implications for understanding the role of these ‘typical’ RBD mutations and the new Omicron-specific RBD mutations in the rapid spread of the virus, as well as for developing new approaches to prevent their global spread.

The study was supported by the Science and Technology Development Fund of Macao, the University of Macau (UM), the Faculty of Health Sciences (FHS) of UM, and the UM Macao Talent Programme.

Articles in the Academic Research column were submitted by UM scholars. The views expressed are solely those of the author(s).

Dr Siddharth Sinha is a postdoctoral researcher in Prof San Ming Wang’s laboratory in FHS of UM. He obtained his PhD in biochemistry and molecular biology from TERI University in New Delhi, India. He specialises in protein structure analysis and high-throughput simulations.

Dr Benjamin Tam is a postdoctoral researcher in Prof San Ming Wang’s laboratory in FHS of UM. He obtained his PhD in Chemical Engineering from University College London, United Kingdom. Dr Tam is a recipient of the UM Macao Postdoctoral Fellowship. He specialises in protein structure analysis, machine learning and high‑throughput simulations.

Prof San Ming Wang is a professor in FHS of UM. He holds an MD in genetics from the Swiss Institute for Experimental Cancer Research / University of Lausanne, Switzerland. He specialises in cancer genetics and prevention.

ISSUE25 | 2022

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