̽��ֱ�� of Cambridge - Geoffrey Smith

Treatments for poxviruses – including those causing mpox and smallpox – may already exist in licensed drugs

jg533 — Wed, 09 Aug 2023 15:00:56 +0000

Scientists studying how poxviruses evade natural defences in human cells have identified a new approach to treatment that may be more durable than current treatments.

This follows their discovery of how poxviruses exploit a cellular protein to evade the host cell defences, and thereby replicate and spread effectively.

Existing drugs developed to be immunosuppressive, or treat other viral infections target this cellular protein. ̽��ֱ��team found that these drugs can also restrict the replication and spread of poxviruses.

This approach to treatment, in which the drug does not directly target the virus, means that it will be much more difficult for the virus to evolve drug-resistance.

And because this hijacking mechanism is the same across many poxviruses, the drugs will be effective in treating a range of diseases such as mpox and smallpox.

̽��ֱ��research is published today in the journal Nature.

Despite the fact that smallpox has been eradicated as a disease since 1979, the virus that causes it, variola, is still held in two high security labs – one in the United States, and one in Russia. ̽��ֱ��threat of variola virus being used in bioterrorism has led to a drug, tecovirimat, being licensed to treat smallpox.

There is an ongoing epidemic of mpox (caused by monkeypox virus): although the number of infections has dropped in the UK it is still present, particularly in London, and in many other nations.

Tecovirimat has been used to treat severe cases of mpox over the last year, but this has resulted in the emergence of multiple drug-resistant strains of the monkeypox virus.

“ ̽��ֱ��drugs we identified may be more durable than the current treatment for monkeypox – and we expect will also be effective against a range of other poxviruses including the one that causes smallpox,” said Professor Geoffrey L. Smith, who conducted the work in the Department of Pathology at the ̽��ֱ�� of Cambridge, the Dunn School of Pathology, ̽��ֱ�� of Oxford and the Pirbright Institute.

Once a poxvirus infects a host cell, it has to defend itself from attack by cellular proteins that would restrict virus replication and spread. Researchers identified a specific cell protein, called TRIM5α, that restricts virus growth – and another cellular protein called cyclophilin A that prevents TRIM5α doing so. Existing drugs target cyclophilin A, and so make the virus more sensitive to TRIM5α.

“There are various drugs that target cyclophilin A, and because many of them have gone through clinical trials we wouldn’t be starting from scratch but repurposing existing drugs, which is much quicker,” said Smith.

Many other poxviruses affect animals, for example a global pandemic of ‘Lumpy skin disease’ is currently affecting cattle – and can be fatal.

Smith added: “Our results were completely unexpected. We started the research because we’re interested in understanding the basic science of how poxviruses evade host defences and we had absolutely no idea this might lead to drugs to treat monkeypox virus and other poxviruses.”

Professor Guy Poppy, Interim Executive Chair at the Biotechnology and Biological Sciences Research Council (BBSRC), said: “ ̽��ֱ��national monkeypox consortium was borne out of an urgent need for the UK to respond to an emerging threat of disease caused by this virus. It is critical that public funders and policy makers are able to act with agility and coordination to support a swift scientific response.

“Taking a One Health approach, the rapid response by BBSRC and the Medical Research Council (MRC), in collaboration with policy makers via the UKRI Tackling Infections strategic theme, enabled leading researchers from across the UK to pool their expertise and deliver impactive results at pace.”

̽��ֱ��research was funded by the Department of Pathology, ̽��ֱ�� of Cambridge, ̽��ֱ��Isaac Newton Trust, MRC, Wellcome and a UKRI BBSRC consortium grant awarded in 2022 in response to the mpox outbreak.

Reference

Zhao et al.: ‘TRIM5α restricts poxviruses and is antagonized by CypA and viral protein C6.’ Nature, August 2023. DOI: 10.1038/s41586-023-06401-0

̽��ֱ��science behind the discovery

̽��ֱ��project started with the simple observation that vaccinia virus infection causes a reduction in the level of TRIM5α in human cells. To find out why, the team engineered human cells to lack TRIM5α and found that in these cells the virus replicated and spread better. This shows that TRIM5α has anti-viral activity.

Next they identified the vaccinia virus protein that TRIM5α targets. They also discovered that the virus has two defences against attack by TRIM5α: first, it exploits another cellular protein, cyclophilin A, to block the antiviral activity of TRIM5α, and second it makes a protein, C6, that induces destruction of TRIM5α.

Existing drugs target cyclophilin A. When the team tested a series of these drugs against a range of poxviruses, including monkeypox, they had antiviral effects in all cases. ̽��ֱ��drugs work by making the virus more sensitive to TRIM5α.

Scientists have discovered how poxviruses evade natural defences in living cells, and realised that drugs to stop them doing this are already available.

̽��ֱ��drugs we identified may be more durable than the current treatment for monkeypox...and also effective against a range of other poxviruses

Geoffrey Smith

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Monkeypox virus

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Cambridge researchers join new £2 million UK consortium to tackle monkeypox outbreak

cjb250 — Wed, 19 Oct 2022 23:01:27 +0000

̽��ֱ��consortium has received £2 million from the Biotechnology and Biosciences Research Council and the Medical Research Council, both part of UK Research and Innovation (UKRI). It is led by the Pirbright Institute and the MRC- ̽��ֱ�� of Glasgow Centre for Virus Research.

Researchers will work closely with experts at government agencies – the Animal and Plant Health Agency, UK Health Security Agency, and Defence Science and Technology Laboratory – to study the current outbreak and inform the public health response in the UK and internationally.

Cambridge scientists Professor Geoffrey Smith from the Department of Pathology and Professor Mike Weekes from the Cambridge Institute for Medical Research and Department of Medicine are among the key scientists involved in the consortium.

Professor Weekes said: "Monkeypox has become a really important global pathogen, reaching more than 50 countries worldwide in a matter of months. Although we have an effective vaccine and treatment, global roll-out has so far proved challenging, emphasising the importance of a comprehensive understanding of this virus. ̽��ֱ��UK consortium includes researchers from multiple different disciplines, and I anticipate the data we generate will rapidly help understand how the virus can be targeted in new ways to prevent disease."

Professor Smith said: “Few would have predicted that monkeypox virus would be causing a global epidemic in 2022. ̽��ֱ��ability to respond quickly to this new challenge has been helped greatly not just by the swift and welcome response of UKRI, but also by decades of support for the study of orthopoxviruses from UKRI and the Wellcome Trust. ̽��ֱ��information gained from those studies is valuable in the fight against monkeypox virus.”

̽��ֱ��monkeypox virus outbreak originated in West Africa. ̽��ֱ��current worldwide outbreak of cases spreading outside this area was first identified in May 2022. This is the first time that many monkeypox cases and clusters have been reported in non-endemic areas.

In the UK there have been more than 3,400 confirmed cases since May, although case numbers are currently falling. Internationally, WHO reports it has spread to 106 countries and territories with 25 confirmed deaths.

Professor Melanie Welham, Executive Chair of BBSRC, said: “One of the real strengths of the UK’s scientific response to disease outbreaks is the way that we can draw on leading researchers from all over the country, who can pool their expertise to deliver results, fast. Long-term support for animal and human virus research has ensured we have the capability to respond with agility.

“This new national consortium will study the unprecedented monkeypox outbreak to better understand how to tackle it. This will feed rapidly into global public health strategies, developing new diagnostic tests and identifying potential therapies.”

̽��ֱ��consortium will focus on building our understanding in a number of key areas, including:

Developing new tests and identifying potential control measures:

Developing sensitive point-of-care tests to speed up diagnosis, such as lateral flow tests or LAMP* tests. ̽��ֱ��lateral flow test development will be conducted with Global Access Diagnostics (GADx) to develop a product which could later be manufactured at scale and used clinically worldwide, including in low/middle income countries.
Screening potential drugs to treat monkeypox in human cells in the lab to determine which ones could be developed for further testing.
Studying the virus, how it infects humans and its susceptibility to the immune response to identify targets for future therapies.

Studying the virus:

Characterising the genome of the virus and studying how it is evolving, and how this is linked to changes in the transmission and pathology of the virus.
Understanding the human immune response to the virus and the vaccine, including studying samples from infected individuals.
Identifying animal reservoirs and potential spill-over routes of transmission between animals and humans.

Learning from the vaccine roll-out:

Studying the effectiveness of the smallpox vaccine by tracking the immune responses after primary and secondary vaccination of up to 200 individuals.

Professor Bryan Charleston, co-lead from ̽��ֱ��Pirbright Institute, said: “ ̽��ֱ��implications of the current monkeypox outbreak are huge. As well as tackling the current outbreak, we also need to be fully prepared for next outbreak, because worldwide there’s a huge reservoir of infection. One of the key ways we can do this is to develop rapid tests, which are very important to help clinicians on the front line to manage the disease.”

Professor Massimo Palmarini, co-lead from the MRC- ̽��ֱ�� of Glasgow Centre for Virus Research, said: “Monkeypox is public health challenge, so taking decisive, collective action to better understand this virus is paramount. By bringing together research expertise in different areas, we will harness the UK’s world-leading knowledge to learn more about how the virus works and spreads and provide the foundations for the development of potential new treatments.”

Adapted from a press release from UKRI

Cambridge is among 12 institutions across the UK that will be working together to tackle the monkeypox outbreak, developing better diagnostic tests, identifying potential therapies and studying vaccine effectiveness and the virus’ spread.

Few would have predicted that monkeypox virus would be causing a global epidemic in 2022

Geoffrey Smith

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Monkeypox virus - 3D render

̽��ֱ��text in this work is licensed under a Creative Commons Attribution 4.0 International License. Images, including our videos, are Copyright © ̽��ֱ�� of Cambridge and licensors/contributors as identified. All rights reserved. We make our image and video content available in a number of ways – as here, on our main website under its Terms and conditions, and on a range of channels including social media that permit your use and sharing of our content under their respective Terms.

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