Nature: A deeper look at how SARS-CoV-2 communicates with human cells

Contact maps published in the journal Nature Biotechnology reveal direct contact or protein interactions
between more than 200 proteins.
An international consortium of scientists led by Dr.
Pascal Falter-Braun, Director of the Helmholtz Institute for Cyberbiology (INET) in Munich and Professor at the School of Biology at the Ludwig-Maximilian University (LMU), includes teams
from Canada, the United States, France, Spain and Belgium.

Scientists at the Laboratory of Structural Bioinformatics and Network Biology, led by Dr.
Patrick Aloy, IRB ICREA Research Professor in Barcelona, contributed
to this work by analysing the network of interactions between viruses and human cells.
They found that many viral proteins showed a binding preference for specific domains that are present in
a variety of human proteins.

"Thanks to our expertise in structural biology, we were able to add a structural layer to the contact network, providing valuable insights," said
Dr.
Carles Pons, an associate researcher in the lab.

"A better understanding of how viruses interact with our cells is key
to pharmacologically preventing them.
In fact, this consortium has successfully tested some compounds
.
Further research will now focus on assessing how genetic variability in the human host affects these interactions
," explains Dr Aloy.

In contrast to previous large-scale studies of protein-protein associations, direct protein contact
between viruses and hosts can now be precisely identified.
Dr Frederick Roth, professor at the Donnelly Centre and Sinai Health Centre at the University of Toronto (Toronto, Canada), said: "To truly understand the mechanistic links between viruses and hosts, we need to know how these pieces fit together
.
"

By taking a closer look at this newly discovered set of direct protein interactions (or "contact groups"), the team discovered the linkage between
viral proteins and human genes associated with infection.
For example, they were able to trace the link between certain SARS-CoV-2 proteins and human proteins encoded by genes, which in other studies have been linked to
an increased likelihood of severe COVID-19.
They also found links between viral proteins and genes, for example, involved in metabolic disorders such as obesity and diabetes
.
Dr Falter-Braun said: "We already know that genetic differences in humans play an important role
in the course and severity of COVID-19 infection.
Thanks to the identification of molecular contact points, it is now possible to examine the underlying mechanisms
.
"Initial insights include demonstrating that important inflammatory signaling pathways are directly activated by viruses
.
These exposures may help explain the exaggerated inflammatory response
that plays an important role in severe cases of COVID-19.
However, the contact between the proteins points not only to the function of human cells and the human immune system, but also to the function of SARS-CoV-2, including the speed of
viral replication.
The interaction of viruses and human cells can be thought of as a visit by the virus to the restaurant: the guest - the virus - initially only comes into contact with the waiter, but then, the waiter goes to the kitchen, communicates the order to the chef, and the virus is answered again, which in this case in turn affects the virus
.
Depending on the proteins in human cells – i.
e.
, waiters, cooks, kitchen assistants, etc.
– that encounter the protein of the virus, the infection and immune response may be different
.

"Because of this interaction of protein-protein linkages, our systematic contact map points to a number of potential drug targets," said
Dr.
Falter-Braun.
For example, scientists have been able to show that the human protein USP25 is recruited to help certain viral processes, and its inhibition significantly reduces the virus's reproduction
.
"Many of the technologies and collaborations in this study were developed for other purposes and then quickly 'pivoted' to the COVID-19 pandemic, highlighting the value of basic research investments," said Dr.
Dae-Kyum Kim, lead
author of the study.
To do this, they first have to put in some effort, using the latest technology, because mapping contacts can sometimes feel like solving a huge puzzle for international research teams
.
The scientists systematically examined and demonstrated interactions between about 30 viral proteins, each of which was subjected to a so-called analysis with about 17,500 human proteins, carefully screening 450,000 pairs of proteins
.

With their hands, it is impossible for anyone to achieve such an achievement
in such a short period of time.
"When we perform multiple assays on a single Petri dish, we turn to robotics so that each protein type is automatically paired
with the other.
We use artificial intelligence methods to initially assess whether an interaction has occurred," says
Dr.
Falter-Braun.

Such a huge project requires teamwork
.
"From molecular biology methods to computational analysis of networks and protein domains, to expertise in virology and innate immunity, we collaborate across disciplines," says
Dr.
Falter-Braun.
Dr Caroline Demeret, from the Institut Pasteur, said: "Our expertise in the combination of virus-host interaction omics and RNA virus biology allows us to assess the dependence
of viruses on direct partners of the host.
" The researchers believe the effort is worth it
.
Contact Atlas will serve as a platform for the scientific community to study interactions between individuals in greater detail and understand their impact on molecular mechanisms and clinical progress, leading to the discovery of a starting point
for new therapeutic strategies.

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