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University of Cambridge scientists show targeting cellular response to Covid-19 is effective in the lab



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Cambridge scientists have found an “exciting” new treatment approach against the Covid-19 virus that is effective in laboratory models.

The anti-viral treatment focuses on fixing cell damage, rather than fighting the virus directly - and if it proves to be safe for human use it is believed it would make symptoms milder and speed up recovery times.

Colorised scanning electron micrograph of an apoptotic cell (red) heavily infected with SARS-COV-2 virus particles (yellow), isolated from a patient sample. Image captured at the NIAID Integrated Research Facility (IRF) in Fort Detrick, Maryland. Image: NIAID (48445785)
Colorised scanning electron micrograph of an apoptotic cell (red) heavily infected with SARS-COV-2 virus particles (yellow), isolated from a patient sample. Image captured at the NIAID Integrated Research Facility (IRF) in Fort Detrick, Maryland. Image: NIAID (48445785)

The virus invades our cells and uses them to replicate, putting cells under stress.

Current approaches to dealing with infection by the SARS-CoV-2 virus target the virus using anti-viral drugs.

But the new approach from University of Cambridge scientists targets the body’s cellular response instead.

Publishing their study in the journal PLOS Pathogens, the team explains that all branches of a three-pronged signalling pathway called the ‘unfolded protein response’ (UPR) are activated in lab-grown cells infected with the virus.

This scanning electron microscope image shows SARS-CoV-2 (yellow), the virus that causes Covid-19 - isolated from a patient in the US, emerging from the surface of cells (blue/pink) cultured in the lab. Image: National Institute of Allergy and Infectious Diseases-Rocky Mountain Laboratories, NIH (48445794)
This scanning electron microscope image shows SARS-CoV-2 (yellow), the virus that causes Covid-19 - isolated from a patient in the US, emerging from the surface of cells (blue/pink) cultured in the lab. Image: National Institute of Allergy and Infectious Diseases-Rocky Mountain Laboratories, NIH (48445794)

Using drugs to Inhibit the UPR and restore normal cell function was shown to reduce virus replication significantly.

Senior author Dr Nerea Irigoyen, in the Department of Pathology, said: “The virus that causes Covid-19 activates a response in our cells - called the UPR - that enables it to replicat.

“Using drugs we were able to reverse the activation of this specific cellular pathway, and remarkably this reduced virus production inside the cells almost completely, which means the infection could not spread to other cells. This has exciting potential as an anti-viral strategy against SARS-CoV-2.”

They found some effect from treatment with a drug that targets one prong of the UPR pathway. Simultaneously targeting two prongs using two drugs - Ceapin-A7 and KIRA8 - reduced virus production in the cells by 99.5 per cent.

This is the first study to show the combination of two drugs has a much greater effect on virus replication in cells than a single drug.

This scanning electron microscope image shows SARS-CoV-2 (yellow), the virus that causes Covid-19 - isolated from a patient in the US, emerging from the surface of cells (blue/pink) cultured in the lab. Image: National Institute of Allergy and Infectious Diseases-Rocky Mountain Laboratories, NIH
This scanning electron microscope image shows SARS-CoV-2 (yellow), the virus that causes Covid-19 - isolated from a patient in the US, emerging from the surface of cells (blue/pink) cultured in the lab. Image: National Institute of Allergy and Infectious Diseases-Rocky Mountain Laboratories, NIH

While it would not stop infection, this approach would make symptoms much milder and speed up recovery.

There is a danger that the virus could develop resistance to current drugs such as remdesivir that target replication of the virus itself.

But the new approach targets the response of the infected cells, which would not change even if new variants emerge as the virus relies on this very cellular response to replicate.

The treatment will now be tested in mouse models, and the researchers also want to see whether it works against other viruses, and illnesses such as pulmonary fibrosis and neurological disorders that also activate the UPR response in cells.

Colorised scanning electron micrograph of a cell heavily infected with SARS-CoV-2 virus particles (yellow), isolated from a patient sample. The black area in the image is extracellular space between the cells. Image captured at the NIAID Integrated Research Facility (IRF) in Fort Detrick, Maryland. Image: NIAID (48445790)
Colorised scanning electron micrograph of a cell heavily infected with SARS-CoV-2 virus particles (yellow), isolated from a patient sample. The black area in the image is extracellular space between the cells. Image captured at the NIAID Integrated Research Facility (IRF) in Fort Detrick, Maryland. Image: NIAID (48445790)

“We hope this discovery will enable the development a broad-spectrum anti-viral drug, effective in treating infections with other viruses as well as SARS-CoV-2. We’ve already found it has an effect on Zika virus too. It has the potential to have a huge impact,” said Dr Irigoyen.

The research was funded by an Isaac Newton Trust, Wellcome Trust ISSF and University of Cambridge joint research grant.

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