Building synthetic virus particles to study SARS-CoV-2

Date:
February 22, 2022
Source:
Max-Planck-Gesellschaft
Summary:
Researchers create minimalistic Sars-CoV-2 virions and discover
the spike protein switching mechanism.



FULL STORY ========================================================================== Scientists at the Max Planck Institute for Medical Research in
Heidelberg and their collaborators at 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 research
of Sars-CoV-2 they built minimalistic synthetic virus particles where
they can incorporate distinct structures of the Sars-CoV-2 virus like
the spike protein. This allowed scientists to study single molecular
mechanisms in a controlled setting, which they can further manipulate
and tune. Using this technique to study the spike protein, which has
been shown to be critical for virus-host interaction and infection,
they discovered a switching mechanism. Upon binding of inflammatory fatty acids, the spike protein changes its conformation, thereby becoming less "visible" to the hosts immune system.


==========================================================================
The Sars-CoV-2 pandemic has been and is still one of the main global
health concerns. Completely understanding Sars-CoV-2 pathogenesis and the molecular mechanisms behind the infection yields great opportunities to overcome the pandemic. Shedding light upon viral functions and host-virus interactions will facilitate the development of targeted therapies,
vaccines or other preventive measures. However, research on Sars-CoV-2
in the laboratory environment comes with many challenges. One is the
increased safety requirement for experiments, another is studying distinct mechanisms during the infection rather than the whole pathogenesis to
better understand those single processes.

Building artificial SARS-CoV-2 virions Researchers at the Max Planck
Institute for Medical Research and their collaborators used their
expertise in bottom-up synthetic biology to overcome some of those
challenges. For their study, they developed artificial Sars-CoV- 2
virions. The virions have a similar structure to natural viruses but do
not contain any genetic information. Therefore, they can be used safely.

"Even more important for us, as we build these synthetic virions
from scratch, is that we can precisely design their composition and
structure. This allows us to perform a very systematic, step-by-step
study on distinct mechanisms," says Oskar Staufer, first author of the
paper, former postdoc at the Max Planck Institute for Medical Research
and current postdoc at the University of Oxford.

He therefore sees great potential in using the synthetic virus-like
particles in a multitude of analysis and characterization pipelines to
study viruses beyond the current application for Sars-CoV-2.

Spike protein switching mechanism to avoid the immune system? They
first used the artificial minimalistic 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 immune response and healing processes. The spike protein is
critical for host- virus interaction. On the one hand the virus uses the
spike protein to bind to the host cells ACE2 receptors. This enables 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, thereby marking the virus a target for the immune system.

It was known before, that the spike protein has a distinct region where inflammatory fatty acids can bind. However, the function of this binding
pocket was previously not understood. Researchers at the Max Planck
Institute for Medical Research and collaborators in Bristol now used
the artificial Sars-CoV- 2 virions to study this exact mechanism. They
show that upon binding of a fatty acid, the spike protein changes its conformation and "folds." As a result, binding to the ACE2 receptor of the
host is no longer possible and fewer antibodies can bind to the protein.

Researchers can now start to understand why this cowering mechanism is
used by the virus and determine whether this information can be used to
develop therapeutic strategies. "By "ducking down" of the spike protein
upon binding of inflammatory fatty acids, the virus becomes less visible
to the immune system.

This could be a mechanism to avoid detection by the host and a strong
immune response for a longer period of time and increase total infection efficiency," says Oskar Staufer. However, scientists are just at the
beginning of determining the function of the folding mechanism, but the
use of artificial virions will allow for a systematic approach. "Applying
such synthetic biology concepts to a problem with global impact is truly exciting!," says Oskar Staufer.

========================================================================== Story Source: Materials provided by Max-Planck-Gesellschaft. Note:
Content may be edited for style and length.


========================================================================== Journal Reference:
1. Oskar Staufer, Kapil Gupta, Jochen Estebano Hernandez Bu"cher,
Fabian
Kohler, Christian Sigl, Gunjita Singh, Kate Vasileiou, Ana
Yagu"e Relimpio, Meline Macher, Sebastian Fabritz, Hendrik Dietz,
Elisabetta Ada Cavalcanti Adam, Christiane Schaffitzel, Alessia
Ruggieri, Ilia Platzman, Imre Berger, Joachim P. Spatz. Synthetic
virions reveal fatty acid- coupled adaptive immunogenicity of
SARS-CoV-2 spike glycoprotein. Nature Communications, 2022; 13
(1) DOI: 10.1038/s41467-022-28446-x ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2022/02/220222151831.htm

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