̽��ֱ�� of Cambridge - ̽��ֱ��Pirbright Institute

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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Study identifies genetic changes likely to have enabled SARS-CoV-2 to jump from bats to humans

jg533 — Fri, 08 Jan 2021 14:56:53 +0000

̽��ֱ��genetic adaptions identified were similar to those made by SARS-CoV - which caused the 2002-2003 SARS epidemic - when it adapted from bats to infect humans. This suggests that there may be a common mechanism by which this family of viruses mutates in order to jump from animals to humans. This understanding can be used in future research to identify viruses circulating in animals that could adapt to infect humans (known as zoonoses) and which potentially pose a pandemic threat.

“This study used a non-infectious, safe platform to probe how spike protein changes affect virus entry into the cells of different wild, livestock and companion animals, something we will need to continue monitoring closely as additional SARS-CoV-2 variants arise in the coming months,” said Dr Stephen Graham in the ̽��ֱ�� of Cambridge’s Department of Pathology, who was involved in the study.

In the 2002-2003 SARS epidemic, scientists were able to identify closely related isolates in both bats and civets – in which the virus is thought to have adapted to infect humans. However, in the current COVID-19 outbreak scientists do not yet know the identity of the intermediate host or have similar samples to analyse. But they do have the sequence of a related bat coronavirus called RaTG13 which shares 96 percent similarity to the SARS-CoV-2 genome. ̽��ֱ��new study compared the spike proteins of both viruses and identified several important differences.

SARS-CoV-2 and other coronaviruses use their spike proteins to gain entry to cells by binding to their surface receptors, for example ACE2. Like a lock and key, the spike protein must be the right shape to fit the cell’s receptors, but each animal’s receptors have a slightly different shape, which means the spike protein binds to some better than others.

To examine whether these differences between SARS-CoV-2 and RaTG13 were involved in the adaptation of SARS-CoV-2 to humans, scientists swapped these regions and examined how well these resulting spike proteins bound human ACE2 receptors - using a method that does not involve using live virus.

̽��ֱ��results, published in the journal PLOS Biology, showed SARS-CoV-2 spikes containing RaTG13 regions were unable to bind to human ACE2 receptors effectively, while the RaTG13 spikes containing SARS-CoV-2 regions could bind more efficiently to human receptors - although not to the same level as the unedited SARS-CoV-2 spike protein. This potentially indicates that similar changes in the SARS-CoV-2 spike protein occurred historically, which may have played a key role in allowing the virus to jump the species barrier.

Researchers also investigated whether the SARS-CoV-2 spike protein could bind to the ACE2 receptors from 22 different animals to ascertain which of these, if any, may be susceptible to infection. They demonstrated that bat and bird receptors made the weakest interactions with SARS-CoV-2. ̽��ֱ��lack of binding to bat receptors adds weight to the evidence that SARS-CoV-2 likely adapted its spike protein when it jumped from bats into people, possibly via an intermediate host.

Dog, cat, and cattle ACE2 receptors were identified as the strongest interactors with the SARS-CoV-2 spike protein. Efficient entry into cells could mean that infection may be more easily established in these animals, although receptor binding is only the first step in viral transmission between different animal species.

“As we saw with the outbreaks in Danish mink farms last year, it’s essential to understand which animals can be infected by SARS-CoV-2 and how mutations in the viral spike protein change its ability to infect different species,” said Graham.

An animal’s susceptibility to infection and its subsequent ability to infect others is reliant on a range of factors - including whether SARS-CoV-2 is able to replicate once inside cells, and the animal’s ability to fight off the virus. Further studies are needed to understand whether livestock and companion animals could be receptive to COVID-19 infection from humans and act as reservoirs for this disease.

This research was funded by the Medical Research Council, the Biotechnology and Biological Sciences Research Council and Innovate UK - all part of UK Research and Innovation; the Royal Society and Wellcome.

Reference
Conceicao, C et al: ‘ ̽��ֱ��SARS-CoV-2 Spike protein has a broad tropism for mammalian ACE2 proteins’. PLOS Biology, Dec 2020. DOI:10.1371/journal.pbio.3001016

Adapted from a press release by the Pirbright Institute

A new study, involving the ̽��ֱ�� of Cambridge and led by the Pirbright Institute, has identified key genetic changes in SARS-CoV-2 - the virus that causes COVID-19 - that may be responsible for the jump from bats to humans, and established which animals have cellular receptors that allow the virus to enter their cells most effectively.

It is essential to understand which animals can be infected by SARS-CoV-2 and how mutations in the viral spike protein change its ability to infect different species

Stephen Graham

orientalizing on Flickr

Horseshoe bats

̽��ֱ��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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African Horse Sickness: mapping how a deadly disease might spread in the UK

amb206 — Sat, 25 May 2013 07:00:00 +0000

As its name suggests, African Horse Sickness (AHS) is associated with the continent of Africa, where it is feared as a deadly disease. It has long been assumed by British veterinarians and horse-owners that the disease, which is carried by midges, could not spread to cooler northern climates.

But researchers now think that its arrival in northern Europe could be only a matter of time – and perhaps more importantly, that it could spread if it did arrive.

A study undertaken by scientists at the ̽��ֱ�� of Cambridge Department of Veterinary Medicine, in collaboration with the Animal Health Trust and ̽��ֱ��Pirbright Institute, shows how dangerous it could be for the horse and pony population if AHS was introduced into the UK. ̽��ֱ��research also identified which regions would be worst hit at different times of the year.

This information could be vital to strategies for coping with an outbreak if it arrived. ̽��ֱ��study also emphasises the importance of the continued exclusion of the disease.

̽��ֱ��research was led by Dr Gianni Lo Iacono, a multidisciplinary scientist whose expertise lies in the mathematical modelling of a range of problems related to the interface between biology and physics. He worked with a team of colleagues from complementary fields including Professor James Wood, a renowned specialist in infectious diseases.

Most strikingly, East Anglia emerges from the study as the region that is most vulnerable to AHS spread which could occur if the disease was not identified early enough for action to be taken to contain it.

In Africa, the disease is spread by infected insects from species of midge known as Culicoides imicola, which carry the African Horse Sickness virus, an orbivirus of the family Reoviridae. Once a horse is infected by AHS, there is no treatment and no cure: the animal will have a high fever within 24 hours and most infected animals will be dead within 48 hours.

Other equidae, zebras and donkeys, are susceptible to AHS infection but do not have such severe disease. Infected zebras do not exhibit any apparent symptoms: as seemingly healthy animals they are potentially lethal carriers. Donkeys develop symptoms but can survive the disease.

First recorded references of AHS occurred in 1327 in Yemen, and in the mid-1600s following the introduction of horses to southern Africa. ̽��ֱ��disease was clearly identified by the British Army in South Africa 150 years ago when scores of cavalry horses perished in an epidemic.

Ever since, European horse owners have taken comfort from the fact that the disease could not strike in cooler countries. ̽��ֱ��British climate was considered too cold for the Culicoides imicola midges to survive. On top of this, the UK (and Europe more generally) has protective mechanisms in place that prohibit horses from Africa entering the country.

A growing number of veterinarians now believe that AHS can now arrive in the UK. Well-documented outbreaks were reported in Morocco (1965, 1989–1991), Spain (1987, 1988,1990) and Portugal (1989). ̽��ֱ��British climate is warming and global transportation of perishable fresh goods – such as flowers and vegetables – offers a possible route for infected midges to enter the country.

̽��ֱ��prospect of AHS brings sharply into focus the need for greater research into ways of preventing an incursion of AHS – and ways to cope in the event of an outbreak. “Our work demonstrates that there is no place for complacency about the ability of the virus to spread here,” said Professor Wood.

A greater understanding of AHS requires a multi-stranded approach covering the behaviour and life cycle of the midge and the geographical distribution and movement of horses, plus possible routes for infection to enter the country. Midge numbers and activity are highest during the warmer summer months, when the arrival of infection from overseas would be most serious.

In the UK, all horses have passports as a legal requirement but these documents record the owners’ address rather than the location where their animals are kept. If horses were mapped according to their owners address, London, for example, would emerge as the centre with the densest horse population. Clearly most horses owned by Londoners are kept outside the city, many of them within easy driving distance of their owners’ homes.

Correcting this issue posed problems. However, satellite data on land usage and a survey which recorded the distribution of distances between horses and their owners in different land-use settings (people live closer to their horses in rural areas than they do in urban areas) allowed the researchers to produce a more meaningful map of the risk of the disease. This showed that East Anglia is particularly vulnerable to an outbreak: not only is the region warm and dry, but it also has distinct clusters of horses, notably around Newmarket.

̽��ֱ��team has also investigated another important aspect of the disease: the possible 'dilution effect' that could be achieved through keeping animals not susceptible to the virus, such as cattle and sheep, close to horses.

Dr Lo Iacono explained: “In some communities in Africa people keep cattle or sheep near their houses in the belief that this will distract mosquitoes carrying malaria away from people. Some midges show apparent preference for cattle over sheep, so in South Africa deploying cattle to protect sheep from bluetongue (a similar disease to AHS in cattle and sheep) has been proposed as a way to control the disease. On the other hand, the presence of other species might well prove to be an added attraction for midges, exacerbating the threat to horses.”

̽��ֱ��research re-emphasises the importance of veterinary education to allow early disease identification, which can reduce the critically important reaction times to allow optimal control.

̽��ֱ��tools that Dr Lo Iacono has developed have potential applications in mapping and responding to the spread of other diseases, some of which are ecologically even more complex – such as Rift Valley Fever, a mosquito-borne disease that affects both humans and animals, causing a serious disease and in some cases death.

̽��ֱ��research provides a good example of how theoretical models can identify biological knowledge gaps (identifying midge biting preferences). This is now being taken forward in other studies.

‘Where are the horses? With the sheep or cows? Uncertain host location, vector-feeding preferences and the risk of African horse sickness transmission in Great Britain’ by Giovanni Lo Iacono, Charlotte Robin, Richard Newton, Simon Gubbins, and James Wood is published by the Journal of the Royal Society, Interface (2013) 20130194 doi:10 .1098/rsif.2013.0194

For more information on this story contact Alex Buxton, Office of Communications, ̽��ֱ�� of Cambridge amb206@admin.cam.ac.uk 01223 761673.

A disease lethal to horses, until now confined to hot countries, could arrive in the UK. New research creates a picture of its possible spread and pinpoints the area that would be worse hit.

Our work demonstrates that there is no place for complacency about the ability of the virus to spread here.

Professor James Wood

Mick Dolphin (Flickr Creative Commons)

Early morning, Newmarket

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