Scientists from the Max Planck Institute for Medical Research in Heidelberg and their collaborators from the Max Planck Bristol Center for Minimal Biology at the University of Bristol have developed a new approach to study Sars-CoV-2. For systematic and standardized Sars-CoV-2 research, they constructed minimalist synthetic virus particles where they can incorporate distinct structures of the Sars-CoV-2 virus like the spike protein.
This allowed scientists to study unique molecular mechanisms in a controlled setting, which they can then manipulate and tune. By using this technique to study the spike protein, which has been shown to be essential for virus-host interaction and infection, they discovered a switching mechanism. Upon binding of inflammatory fatty acids, the spike protein changes conformation, becoming less “visible” to the host’s immune system.
The Sars-CoV-2 pandemic has been and still is one of the major global health issues. Understanding completely the pathogenesis of Sars-CoV-2 and the molecular mechanisms behind the infection offers great opportunities to overcome the pandemic. Shedding light on viral functions and host-virus interactions will facilitate the development of targeted therapies, vaccines or other preventive measures. However, researching Sars-CoV-2 in the laboratory presents many challenges. One is the increased safety requirement for experiments, another is investigating distinct mechanisms during infection rather than entire pathogenesis to better understand these unique processes.
Researchers at the Max Planck Institute for Medical Research and their collaborators used their expertise in bottom-up synthetic biology to overcome some of these challenges. For their study, they developed artificial Sars-CoV-2 virions. Virions are similar in structure to natural viruses but contain no genetic information. Therefore, they can be used safely. “Even more important to us, as we build these synthetic virions from scratch, is that we can precisely engineer their composition and structure. This allows us to perform a very systematic, step-by-step study of distinct mechanisms,” says Oskar Staufer, first author of the paper, former postdoctoral fellow at the Max Planck Institute for Medical Research and current postdoctoral fellow at the University of Oxford. He therefore sees great potential in using the synthetic virus-like particles in a multitude of analytical and characterization pipelines to study viruses beyond the current application for Sars-CoV-2.
They first used the artificial minimalist virions to study the effect of inflammatory fatty acids on the spike protein of Sars-CoV-2. Inflammatory fatty acids are released during any inflammation in the body and they help facilitate the immune response and healing processes. The spike protein is essential for host-virus interaction. For one thing, the virus uses the spike protein to bind to host cell ACE2 receptors. This allows the virus to fuse with the host cell and release its genetic information. On the other hand, antibodies produced by the host can bind to the spike protein, thus marking the virus as a target of the immune system. It was previously known that the spike protein has a distinct region where inflammatory fatty acids can bind. However, the function of this connecting pocket was previously not understood.
Researchers from the Max Planck Institute for Medical Research and collaborators from Bristol have now used Sars-CoV-2 artificial virions to study this exact mechanism. They show that upon binding of a fatty acid, the spike protein changes conformation and “bends”. As a result, binding to the host ACE2 receptor is no longer possible and fewer antibodies can bind to the protein. Researchers can now begin to understand why this fallback mechanism is used by the virus and whether this information can be used to develop therapeutic strategies. “By ‘dodging’ the spike protein when binding inflammatory fatty acids, the virus becomes less visible to the immune system. This could be a mechanism to avoid host detection and a strong immune response for a longer period of time and increase the total efficiency of infection,” says Oskar Staufer. However, scientists are only at the beginning of determining the function of the folding mechanism, but the use of engineered virions will allow a systematic approach. “Applying such synthetic biology concepts to a global impact problem is really exciting!” says Oskar Staufer.
Reference: Staufer O, Gupta K, Hernandez Bücher JE, et al. Synthetic virions reveal the adaptive fatty acid-coupled immunogenicity of the SARS-CoV-2 spike glycoprotein. National communications. 2022;13(1):868. do I: 10.1038/s41467-022-28446-x.
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