Cells hijacked by SARS-CoV-2, a novel coronavirus that causes the COVID-19 disease, grow arm-like extensions, or filopodia, which may explain rapid viral spread throughout the body.
SARS-CoV-2 viruses visible on a cell with filopodia. Image credit: Elizabeth Fischer, Miscroscopy Unit NIH / NIAID.
Viruses are unable to replicate and spread on their own: they need an organism to carry, replicate, and transmit them to further hosts, explained study first author Dr. Mehdi Bouhaddou of Gladstone Institutes and the University of California San Francisco and colleagues.
To facilitate this process, viruses need to take control of their host cells machinery and manipulate it to produce new viral particles. Sometimes, this hijacking interferes with the activity of the hosts enzymes and other proteins.
Once a protein is produced, enzymes can change its 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 a kinase — plays a pivotal role in the regulation of many cell processes, including cell-to-cell communication, cell growth, and cell death.
By altering phosphorylation patterns in the hosts proteins, a virus can potentially promote its own transmission to other cells and, eventually, other hosts.
The researchers used mass spectrometry to evaluate all host and viral proteins that showed changes in phosphorylation after SARS-CoV-2 infection.
They determined 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 upregulation or downregulation — of phosphorylation activity.
The most strongly hijacked kinases include casein kinase II (CK2), kinases within the p38/MAP kinase (p38/MAPK) pathway, cyclin-dependent kinases (CDKs) and phosphatidylinositol 5-kinase (PIKFYVE), all of which fall within a set of cell signaling pathways.
The virus prevents human cells from dividing, maintaining them at a particular point in the cell cycle. This provides the virus with a relatively stable and adequate environment to keep replicating, said co-lead author Dr. Pedro Beltrao, a scientist at the EMBLs European Bioinformatics Institute.
One of the key findings is that infected cells exhibit long, branched, arm-like extensions, or filopodia.
These structures may help the virus reach nearby cells in the body and advance the infection, but further study is warranted.
SARS-CoV-2 (stained for N-protein in red) was discovered inside called filopodia made of actin cytoskeleton filaments (white) as is visible on these microscopic images. Image credit: Robert Grosse, CIBSS, University of Freiburg.
The distinct visualization of the extensive branching of the filopodia once again elucidates how understanding the biology of virus-host interaction can illuminate possible points of intervention in the disease, said co-lead author Dr. Nevan Krogan, Director of the Quantitative Biosciences Institute the University of California San Francisco and Senior Investigator at Gladstone Institutes.
Kinases possess certain structural features that make them good drug targets. Drugs have already been developed to target some of the kinases we identified, so we urge clinical researchers to test the antiviral effects of these drugs in their trials, Dr. Beltrao said.
In some patients, COVID-19 causes an overreaction of the immune system, leading to inflammation. An ideal treatment would relieve these exaggerated inflammatory symptoms while stopping the replication of the virus. Existing drugs targeting the activity of kinases may be the solution to both problems.
The team identified 87 drugs approved by the Food and Drug Administration (FDA) or ongoing clinical trials that target the kinases of interest.
Seven of these compounds, primarily anticancer and inflammatory disease compounds, demonstrated potent antiviral activity in laboratory experiments.
Our data-driven approach for drug discovery has identified a new set of drugs that have great potential to fight COVID-19, either by themselves or in combination with other drugs, and we are excited to see if they will help end this pandemic, Dr. Krogan said
We expect to build upon this work by testing many other kinase inhibitors while identifying both the underlying pathways and additional potential therapeutics that may intervene in COVID-19 effectively, said co-lead author Professor Kevan Shokat, a researcher at the University of California San Francisco.
Mehdi Bouhaddou et al. The Global Phosphorylation Landscape 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.