Cells hijacked by SARS-CoV-2, a new coronavirus that causes COVID-19 disease, grow arm-shaped or filopodia-like extensions, which may explain the rapid viral spread throughout the body.
SARS-CoV-2 virus visible in a cell with filopodia. Image credit: Elizabeth Fischer, NIH / NIAID Miscroscopy Unit.
“Viruses cannot replicate and spread on their own: They need an organism to transport, replicate, and transmit them to other hosts,” said study first author Dr. Mehdi Bouhaddou of the Gladstone Institutes and the University of California, San Francisco and his colleagues.
“To facilitate this process, viruses need to take control of the machinery of their host cell and manipulate it to produce new viral particles. Sometimes this sequestration interferes with the activity of enzymes and other host proteins. “
“Once a protein is produced, enzymes can change their activity by making chemical modifications to its structure.”
“For example, phosphorylation, the addition of a phosphoryl group to a protein by a type of enzyme called kinase, plays a critical role in regulating many cellular processes, including cell-to-cell communication, cell growth, and death. cellular . “
“By altering phosphorylation patterns in host proteins, a virus can potentially promote its own transmission to other cells, and eventually to other hosts.”
The researchers used mass spectrometry to assess all the host and viral proteins that showed changes in phosphorylation after SARS-CoV-2 infection.
They found that 40 of the 332 human proteins that interact with SARS-CoV-2 were significantly differentially phosphorylated.
In addition, they identified 49 human kinases, out of a total of 518, that showed changes, either positive or negative regulation, of phosphorylation activity.
The most strongly sequestered kinases include casein kinase II (CK2), kinases within the p38 / MAP kinase pathway (p38 / MAPK), cyclin-dependent kinases (CDK), and phosphatidylinositol 5-kinase (PIKFYVE), all of which are found within of a set of cellular signaling pathways.
“The virus prevents human cells from dividing, keeping them at a particular point in the cell cycle. This provides the virus with a relatively stable and suitable environment for further replication, “said co-author Dr. Pedro Beltrao, a scientist at EMBL’s European Institute for Bioinformatics.
One of the key findings is that infected cells exhibit long, branched, arm-shaped or filopodia extensions.
These structures can help the virus reach nearby cells in the body and advance infection, but further study is warranted.
SARS-CoV-2 (stained for protein N in red) was discovered inside called filopodia made from actin cytoskeleton filaments (white) as visible in these microscopic images. Image credit: Robert Grosse, CIBSS, University of Freiburg.
“The clear visualization of the extensive branching of filopodia once again clarifies how understanding the biology of virus-host interaction can shed light on potential intervention points in the disease,” said senior co-author Dr. Nevan Krogan, Director of the Institute of Quantitative Biosciences. University of California, San Francisco and principal investigator at the Gladstone Institutes.
“The kinases possess certain structural characteristics that make them good drug targets. Medications have already been developed to target some of the kinases we identified, so we urge clinical researchers to test the antiviral effects of these medications in their trials, “said Dr. Beltrao.
In some patients, COVID-19 causes an overreaction of the immune system, leading to inflammation. An ideal treatment would alleviate these exaggerated inflammatory symptoms while stopping virus replication. Existing drugs targeting kinase activity may be the solution to both problems.
The team identified 87 medications approved by the Food and Drug Administration (FDA) or ongoing clinical trials targeting the kinases of interest.
Seven of these compounds, primarily compounds against cancer and inflammatory diseases, demonstrated potent antiviral activity in laboratory experiments.
“Our data-driven approach to drug discovery has identified a new set of drugs that have great potential to combat COVID-19, either on their own or in combination with other drugs, and we are excited to see if they will help end this pandemic, “said Dr. Krogan
“We hope to build on this work by testing many other kinase inhibitors while identifying the underlying pathways and potential additional therapies that can effectively intervene in COVID-19,” said co-author lead professor Kevan Shokat, a researcher at the University of California. . San Francisco.
The results appear in the magazine. Cell.
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Mehdi Bouhaddou et al. The global picture of phosphorylation of SARS-CoV-2 infection. Cell, published online June 28, 2020; doi: 10.1016 / j.cell.2020.06.034
This article is based on press releases provided by the European Bioinformatics Institute and the University of Freiburg.
