Explaining the Increased Infectivity of Emerging SARS-CoV-2 Variants

Delta and Omicron mutants of the virus bind more tightly and longer to host cells than early Wuhan variants

February 23, 2023

An international team of researchers working with Gerhard Hummer, director of the Department of Theoretical Biophysics at the Max Planck Institute of Biophysics, studied the attachment of different coronavirus variants to living cells. The scientists found that the Delta and Omicron variants adhere more strongly and longer than the original Wuhan strain of the virus. With this discovery, they explain the increased infectivity and resistance to the host immune system that occurs with the new corona variants.

Text: Katharina Kaefer

Coronavirus Spike Proteins Bind to ACE2 Receptors on the Host Cell Surface

In the infection of cells with the SARS-CoV-2 virus, the spike-shaped proteins on its surface play a crucial role. Spike proteins can be thought of as three-armed grippers that attach to so-called ACE2 receptors naturally occurring on the host cells, allowing the virus to inject its genetic material. In 2020, a research team from the Max Planck Institute (MPI) of Biophysics, in collaboration with the Paul Ehrlich Institute and the European Molecular Biology Laboratory (EMBL), showed that these grippers are not completely rigid, but are connected to the virus via a flexible stalk. This allows several spike proteins to simultaneously "scan" the cell surface in search of ACE2 receptors (Turoňová et al., Science 2020). Furthermore, the spike protein is nearly fully covered with long carbohydrate chains that hamper the host's immune system in identifying the virus as a pathogen. The uncovered regions become antibody targets upon vaccination or infection, leading to rapid viral evolution and appearance of new variants, which escape the immune response by modifying these regions (Sikora et al., Plos Comp Biol 2021, von Buelow et al., Plos Comp Biol 2023). Now, researchers in the Department of Theoretical Biophysics led by Gerhard Hummer at the MPI of Biophysics worked with an international team of experimental experts to investigate how exactly the three-armed spikes bind to the ACE2 receptors. How strong is the binding and how do changes in the spike protein of newer virus variants such as Delta and Omicron influence the binding? They published the answers to these questions in the journal Nature Communications.

The Binding of Spike Proteins to Living Cells was Studied Experimentally and with Computer Simulations

Hummer's team had a look at the binding of spike proteins to cellular ACE2 receptors using molecular dynamics simulations. "We calculate how single spike proteins and the cellular receptors move and how they interact with each other," explains Mateusz Sikora, a postdoctoral researcher in Hummer's department and one of the study's first authors. In collaboration with research groups from Austria, Sweden and Canada, the scientists at the MPI of Biophysics combined their computer simulations with atomic force microscopy (AFM) experiments on living cells (Zhu, Canena, Sikora et al., Nature Communications 2022). AFM uses nanometer-sized hooks to measure forces between molecules by pulling bonds apart, or to rapidly scan surfaces and observe molecular dynamics in real time. Combining the theoretical and experimental methods, the researchers showed that the stalk and, in particular, the three arms of the spike protein are much more flexible than previously thought. Thanks to that, up to three arms can bind to up to three different ACE2 receptors in a very short time. Multiple bindings were observed especially in the original Wuhan strain and the Delta variant. However, a single arm of the Delta spike protein adheres about 10 times more tightly to an ACE2 receptor than an arm of the Wuhan spike. In the case of the Omicron variants, the research team even found an about 100 times stronger binding, but observed less frequent attachment of two or three arms simultaneously.

Improved Binding Properties of Delta and Omicron Spike Proteins Increase Infectivity

"All in all, the virus binds more tightly and longer to the cell surface in both the Delta and Omicron variants," Sikora recaps. "Therefore, the viruses cannot be easily removed by increased blood or mucus flow or reflexes such as coughing or sneezing." This helps explain why the Delta and Omicron variants of the SARS-CoV-2 virus are much more infectious and transmissible compared to the original Wuhan strain.

International Cross-disciplinary Collaboration Brought Success

In containing the Corona pandemic, solidarity and collaboration were key in the international community, and so they are in science. When studying the binding properties of the spike protein, Gerhard Hummer's team used its expertise in molecular dynamics simulations of biophysical systems and phenomena in a collaboration with several renowned international research groups. Peter Hinterdorfer and his team from Johannes Kepler University Linz in Austria conducted the atomic force microscopy experiments, having profound expertise with this technique. Josef M. Penninger from the University of British Columbia in Canada helped to unravel the role of ACE2 receptors in coronavirus infections in 2020, and the team benefited from his knowledge and long experience in medical research. As experts in viral diseases, researchers led by Ali Mirazimi from the Karolinksa Institute in Sweden completed the team. Mateusz Sikora concludes, "For a project like this, you need many people with backgrounds in different fields who complement each other and bring different perspectives to the table. Great science is all about teamwork."

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