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COVID-19 Depends on ‘Master Regulators’ Inside Host Cells to Survive, Finds Study

By HospiMedica International staff writers
Posted on 14 Jul 2020
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Image: COVID-19 Depends on `Master Regulators’ Inside Host Cells to Survive, Finds Study (Photo courtesy of UCSF)
Image: COVID-19 Depends on `Master Regulators’ Inside Host Cells to Survive, Finds Study (Photo courtesy of UCSF)
Scientists have figured out how SARS-CoV-2 hijacks proteins in host cells that serve as master regulators of key cellular processes, allowing the virus to rewire the cell’s internal circuitry for promoting its own spread and survival.

However, this reliance of the virus on host-cell proteins may also prove to be its Achilles’ heel, as these same proteins can be easily targeted with existing drugs. In their study, scientists from the University of California San Francisco (San Francisco, CA, USA) found that when SARS-CoV-2 infects cells, it assumes control over a family of enzymes known as kinases. Under normal circumstances, kinases serve as master regulators of metabolism, growth, movement, repair and other important cellular functions. Kinases work by attaching tiny chemical tags to proteins through a process known as phosphorylation. Once attached, these tags act as switches that turn proteins on or off, which keeps the complex machinery of the cell running smoothly.

The dependence of SARS-CoV-2 on kinases was revealed in experiments in which the researchers counted and catalogued all the proteins found in both infected and uninfected cells. Though they observed no significant differences in the total amount of protein found in each group, the scientists noticed huge disparities in phosphorylation levels – a clear sign that SARS-CoV-2 was changing kinase behavior in infected cells. The researchers found that 49 kinases exhibited abnormal activity in infected cells. In particular, they found that a well-studied kinase network known as the p38/MAPK pathway, which is known to trigger the production of inflammation-inducing cytokines, was significantly more active. This finding may help explain the so-called cytokine storms, which is a hyperactive immune response that damages organs, frequently associated with severe cases of COVID-19. The researchers also found that the CDK kinases, which control the cell cycle, were significantly less active during infection, which halted the resource-intensive process of cell division in order to funnel more resources toward virus production.

However, the most surprising finding was that SARS-CoV-2 activated a kinase called CK2, which in turn appeared to stimulate the production of filopodia, tiny tentacle-like protuberances that extend out from the cell’s surface. Using microscopic techniques, the researchers revealed that SARS-CoV-2 and CK2 “colocalize” in infected cells, likely contributing to the formation of filopodia. With electron microscopy, the researchers zoomed in to capture the first-ever images of the virus budding from these structures. Other viruses, including Ebola, Marburg and vaccinia, are known to give rise to filopodia and to use them as a kind of railway along which those viruses can travel to reach other cells, although this is the first time that filopodia have been observed in association with any member of the coronavirus family. The scientists believe that SARS-CoV-2 may also use filopodia as an infective transport system, although this remains to be confirmed.

After identifying the kinases that SARS-CoV-2 depends on for survival, the scientists compiled a list of existing drugs known to target many of these kinases. If these drugs could successfully interfere with kinase activity in infected cells, they might be able to stop the virus in its tracks. The scientists tested 68 such compounds and found that those that interfered with the activity of the CK2, p38/MAPK and CDK pathways exhibited potent antiviral activity without being toxic to cells, suggesting that a combination “cocktail” of these drugs could prove to be an effective way to treat COVID-19.

“By conducting a systematic analysis of the changes in phosphorylation when SARS-CoV-2 infects a cell, we identified several key factors that will inform not only the next areas of biological study but also treatments that may be repurposed to treat patients with COVID-19,” said Nevan Krogan, PhD, Director of UCSF’s Quantitative Biosciences Institute (QBI), a professor of cellular and molecular pharmacology at UCSF, a senior investigator at Gladstone Institutes and co-senior author of the new study.

“We are encouraged by our findings that drugs targeting differentially phosphorylated proteins inhibited SARS-CoV-2 infection in cell culture,” said Kevan Shokat, PhD, a professor of cellular and molecular pharmacology at UCSF and co-senior author of the study, and a member of QBI Coronavirus Research Group (QCRG), which is a cross-disciplinary team that includes a number of scientists with expertise in kinases, as well as the drugs that can be used to disable them. “We expect to build upon this work by testing many other kinase inhibitors while concurrently conducting experiments with other technologies to identify underlying pathways and additional potential therapeutics that may intervene in COVID-19 effectively.”

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