Startling images reveal coronavirus forming tentacles in cells. It may help identify new treatments.

MILWAUKEE - Amazing, never-before-seen images show that the new coronavirus hijacks proteins in our cells to create monstrous tentacles that branch and can spread infections to neighboring cells.
The finding, accompanied by evidence of potentially more effective drugs against COVID-19, was published on Saturday by an international team of scientists in the journal Cell.
Fluorescence micrograph of human epithelial cells from the colon infected with SARS-CoV-2, the virus that causes COVID-19. The infected cells produce tentacles, formally known as filopodia (in white) that extend from the cell surface and contain viral particles (M protein in red).
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By focusing on the basic behavior of the virus - how it hijacks important human proteins and uses them to benefit itself and harm us - the team was able to identify a family of existing drugs called kinase inhibitors and that COVID-19 appears to offer the most effective treatment to date.
"We have tested a number of these kinase inhibitors and some are better than remdesivir," said Nevan Krogan, one of more than 70 authors of the new paper and director of the Quantitative Biosciences Institute at the University of California, San Francisco.
While remdesivir is not yet approved for use against COVID-19, US regulators allow the drug to be "used on an emergency" basis in hospital patients.
Krogan said tests of kinase inhibitors showed that some, including gilteritnib and ralimetinib, needed lower concentrations than remdesivir to kill 50% of the virus.
The new study, which included experiments on human and other African green monkey cells, shows that the virus, known as SARS-CoV-2, is particularly capable of disrupting vital communication. This communication takes place both within cells and from one cell to another.
Electron micrograph of cells from the kidney of a female African green monkey infected with SARS-CoV-2, the virus that causes COVID-19. Infected cells produce tentacles, formally known as filopodia (orange), that extend from the cell surface to allow virus particle budding (blue) and infection of neighboring cells.
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"This paper shows how completely the virus is able to rewire all the signals in the cell. This is really remarkable and occurs very quickly (as soon as two hours after the cells are infected)," said Andrew Mehle. an associate professor of medical microbiology and immunology at the University of Wisconsin-Madison.
The communication system known as cell signaling enables the growth of cells and the detection and reaction to external threats. Errors in cell signaling can lead to diseases such as cancer and diabetes.
Flour, who was not involved in the study, said the work shows that scientists are struggling with a discouraging enemy in the new Conronavirus. "These are highly efficient, evolutionary machines that make therapeutic development very difficult," he said.
Another try
Since the pandemic started, Krogan and his colleagues have taken a different approach than many researchers looking for treatment for the new virus.
Many scientists have studied thousands of medicines that are already approved for other purposes to determine if they can also be used to treat COVID-19.
"We don't do that," said Krogan. "We say 'let's understand the underlying biology behind how the virus infects us and use it against the virus.' ""
In the search for therapies, many scientists have examined important proteins in the virus - in particular the spike protein, with which the virus cells can bind to human cells.
Fluorescence micrograph of human epithelial cells from the colon infected with SARS-CoV-2, the virus that causes COVID-19. The viral N-protein (red) hijacks the human casein kinase II (green; co-localization in yellow) in order to create suspected branched filopodal protrusions (white outline boxes) that allow the budding of virus particles and the infection of neighboring cells.
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Krogan and his team looked in the opposite direction and focused on human proteins instead of those in the virus. Dozens of human proteins play a vital role in the disease process, as the virus needs them to infect people and make copies of themselves.
It is an important advantage to develop treatments that target human rather than viral proteins. Viral proteins can mutate and develop resistance to the drugs targeted at them. Human proteins mutate far less often.
In April, Krogan and his colleagues published a study in Nature magazine that showed that 332 human proteins interact with 27 viral proteins.
Feixiong Cheng, a doctoral student who heads a laboratory at the Cleveland Clinic Genomic Medicine Institute, described mapping the interactions between these proteins as a "novel" and "powerful" strategy to find existing drugs that could help COVID-19 patients.
In the new study, Krogan's international team looked more closely at biology and focused on how the new coronavirus is changing a complex process called phosphorylation. This process acts as a series of on-off switches for various cell activities, including growth, division, death, and communication among themselves.
"What they did is really a fantastic next step," said Lynne Cassimeris, professor of life sciences at Lehigh University, that the work builds on the previous article and applies the knowledge of cell biology gained over the past 30 years.
"It's an amazing leap. We know the virus has to manipulate these human proteins. Now we have a list of what will change over time."
Cassimeris said that mapping these changes will allow researchers to search for drugs that can intervene at certain points.
The scientists found that the on and off switches in 40 of the 332 proteins that interact with the new corona virus have changed significantly.
The changes occur because the virus chooses 49 enzymes, called kinases, either up or down. By selecting or deselecting kinases, they change 40 of the proteins that interact with the virus.
Think of the kinases as protection against our health until the new coronavirus turns them against us. In any case, the new study identified treatments that could prevent the virus from turning guards into attackers.
The virus most hijacks a kinase called CK2, which plays a key role in the basic structure of the cell, as well as in growth, proliferation and death.
This prompted the scientists to investigate a drug called silmitasertib. Tests have shown that this drug inhibits CK2 and eliminates the new coronavirus.
Electron micrograph of cells from the kidney of a female African green monkey infected with SARS-CoV-2, the virus that causes COVID-19. Infected cells produce tentacles, formally known as filopodia (orange), that extend from the cell surface to allow virus particle budding (blue) and infection of neighboring cells.
More
They also found that the virus has a dramatic effect on a signaling pathway - a group of kinases that form a cascade, similar to falling dominoes. The virus hijacks this cascade, so the end result becomes a dangerous overreaction of our immune system.
The study’s results in this way could help explain the extreme overreaction - a cytokine storm - that causes the immune system to kill both healthy and diseased tissue, leading to more than half of COVID-19 deaths.
Main killer of COVID-19: UW is participating in a drug trial to stop the immune response to wires
Here, too, the scientists were able to identify treatments, including the experimental cancer drug ralimetinib, which can prevent the immune system from overreacting.
The authors of the new study also found that the virus damages a family of kinases called CDKs. These play a role in cell growth and in the response to DNA damage. An experimental drug called Dinaciclib can effectively thwart this virus attack.
Finally, Krogan and his colleagues found that the virus also hijacked a kinase, which helps cells to stay healthy and remove damaged cells in different environments. A small molecule called apilimod targets this kinase and has been able to hinder the virus in laboratory tests.
Krogan, who is also a researcher at UCSF's Gladstone Institute, said the strategy to study the virus-affected human kinases has proven fruitful.
"The kinases are a very drugable set of proteins in our cells," he said.
Follow Mark Johnson on Twitter: @majohnso
This article originally appeared in the Milwaukee Journal Sentinel: Coronavirus cultivates tentacles in cells and provides guidance for treatment

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