Startling, never-before-seen images show that the new coronavirus hijacks proteins in our cells to create monstrous tentacles that branch out and may transmit infection to neighboring cells.
Thefinding, accompanied byevidence ofpotentially more effective drugs against COVID-19,was published Saturday in the journalCellby an international team of scientists.
Fluorescence microscopy image of human epithelial cells taken from the colon and infected with SARS-CoV-2, the virus, that causes COVID-19. The infected cells produce tentacles, known formally as filopodia ( in white) extending out from the cell surface containing viral particles (M protein in red).(Photo: Dr. Robert Gross, University of Freiburg)
By focusing on the fundamental behavior of the virus how it hijacks key human proteins and uses them to benefit itself and harm us the team wasable to identify a family of existing drugs called kinase inhibitors that appear to offerthe most effective treatment yet forCOVID-19.
"We've tested a number of these kinase inhibitors and some are better than remdesivir," said Nevan Krogan, one of more than 70authors of the new paper, and director of the Quantitative Biosciences Instituteat the University of California, San Francisco.
While remdesivir has yet to beapproved for use against COVID-19,U.S.regulatorsare allowing "emergency use" of the drug inhospitalized patients.
Krogan said tests ofkinase inhibitors showed some, including Gilteritnib and Ralimetinib, required lower concentrations thanremdesivir in order tokill off 50% of the virus.
The new study, whichinvolvedexperiments using cells from humans and othersfrom African green monkeys, shows that the virus known as SARS-CoV-2is especially adept at disrupting vital communications. These communicationstake place both withincells and from one cell to another.
Electron microscopy image of cells from the kidney of a female African green monkey that have been infected with SARS-CoV-2, the virus that causes COVID-19. Infected cells produce tentacles known formally as filopodia (orange) extending out from the cell surface to enable budding of viral particles (blue) and infection of nearby cells.(Photo: Dr. Elizabeth Fischer, NIAID/NIH)
"This paper shows just how completely the virus is able to rewire all of the signals going on inside the cell. That's really remarkable and it's something that occurs very rapidly (as soonas twohours after cells are infected)," said Andrew Mehle, an associate professor of medical microbiology and immunology at the University of Wisconsin-Madison.
The communicationssystemknown ascell signaling, allowscells to grow, and to detect and respond to outside threats. Errors in cell signaling can lead to such illnesses as cancer and diabetes.
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Mehle, who was not involved in the study, said the work shows that scientists are contending with a daunting enemy in thenew conronavirus. "These are highly efficient, evolutionarily-tuned machines that will make it very challenging to develop therapeutics," he said.
From early in the pandemic, Krogan and his colleagues have taken adifferentapproach from that of manyresearchers seeking treatments for the new virus.
Many scientists have been screeningthousands of drugs already approved for other uses to determine if theycan also be used to treat COVID-19.
"We're not doing that," Krogan said. "We're saying 'Let's understand the underlying biology behind how the virus infects us, and let's use that against the virus.'"
In thesearch for treatments, many scientists have homed inonkey proteins in the virus especially the Spike protein, which allowsthe viral cellsto attach themselves to human cells.
Fluorescence microscopy image of of human epithelial cells taken from the colon and infected with SARS-CoV-2, the virus that causes COVID-19.Viral N protein (red) hijacks human Casein Kinase II (green; co-localization in yellow) to putatively produce branching filopodia protrusions (white outline boxes) to enable budding of viral particles and infection of nearby cells.(Photo: Dr. Robert Gross, University of Freiburg)
Krogan and his team looked in the opposite direction, focusingon the human proteins, instead of those in the virus. Dozens ofhuman proteins play a critical role in the disease processbecause the virusneeds themto infect people and to make copies of itself.
There is an important advantage to developing treatments aimed atthe human, rather than the viral, proteins. Viral proteins can mutate causing them to develop resistance to the drugs targeted to them. Human proteins are far less likely to mutate.
In April,Krogan and his colleaguespublished a study in the journal Nature showing that332 human proteinsinteract with 27 viral proteins.
Feixiong Cheng, a PhD researcher who runs a lab at Cleveland Clinic Genomic Medicine Institute, called themapping ofinteractions between theseproteins "a novel" and "powerful" strategy for findingexisting drugs that might helpCOVID-19 patients.
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In the new study, Krogan's international teamlooked deeper into the biology, focusing onhow the new coronavirus changes a complex process called phosphorylation. Thisprocess acts as a series ofon-off switches for differentcell activities, includinggrowth, division, deathand communicationwith one another.
"What they've done is really a fantastic next step," said Lynne Cassimeris, a professor of biological sciences at Lehigh University, explaining that the work builds on the previous paper and applies knowledge of cell biologygained over the last30 years.
"It's an amazing leap. We know that the virus has to be manipulating these human proteins. Now we have a list of what is changing over time."
Cassimeris said that mapping these changesallows researchers to seek drugs thatcan intervene at specific points.
The scientists found that on-off switcheschanged significantly in 40 of the 332 proteins that interact with the new coronavirus.
Thechanges occur because the viruseither dialsup or down49 enzymes called kinases. The dialing up or down ofkinases cause them to alter40 of the proteins that interact with virus.
Imagine the kinases as guards protecting our health until the new coronavirus turns them against us. In each case, however, the new study identified treatments that can stopthe virus from turningguards into assailants.
The virus most powerfully hijacks a kinase called CK2, which plays a key role in the basic frameof thecell as well asitsgrowth, proliferation and death.
This led the scientists to investigatea drug called Silmitasertib. Tests found this druginhibits CK2and eliminatesthe new coronavirus.
Electron microscopy image of cells from the kidney of a female African green monkey, which have been infected with SARS-CoV-2, the virus that causes COVID-19. Infected cells produce tentacles known formally as filopodia (blue) extending out from the cell surface to enable budding of viral particles (orange) and infection of nearby cells.(Photo: Dr. Elizabeth Fischer, NIAID/NIH)
They also found that the virus has a dramatic effect on a pathway a group of kinases that forma cascade a little like falling dominoes. The virus hijacksthis cascade so that the end result becomesa dangerous overreaction by ourimmune system.
The study's findingon this pathwaymay help to explainthe extreme overreaction acytokine storm that causes the immune system to kill both healthy anddiseased tissue, leadingtomore than half of the deaths from COVID-19.
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Here too, the scientists were able to identify treatments, including the experimental cancerdrug Ralimetinib, whichmay preventthe immune system overreaction.
Authors of the new study also found that the virus harms a family of kinasescalled CDKs. Theseplay roles incell growth and in the response toDNAdamage. An experimental drug called Dinaciclib may be effective in thwarting thisviral assault.
Finally, Krogan and his colleagues found that the virus also hijack a kinase that helps cells stay healthy in different environments and cleans out damaged cells.A small molecule called Apilimod targets this kinase and has been able to hinderthe virus in lab tests.
Krogan, who is also an investigator at the Gladstone Institutes at UCSF, said the strategy of examining the human kinases affected by the virus has provedfruitful.
"The kinases are a very druggable set of proteins in our cells," he said.
Email him at mark.johnson@jrn.com; follow him on Twitter: @majohnso.
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Study reveals images of the coronavirus forming tentacles in cells -- but monstrous discovery helps identify new treatment - Milwaukee Journal...
