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Could swallowing or inhaling ‘good’ viruses be the new way to beat infections?

Given what we now know about viruses and how potentially lethal they can be, the idea of inhaling or swallowing one to treat an infection sounds like the last thing we would want to do.

But that’s exactly what doctors could soon be prescribing. In fact, you may even be advised to take a virus supplement, much like you would a probiotic, to boost your ‘good’ gut microbes.

But unlike the coronavirus, the viruses used as a treatment or preventative measure only target and kill bacteria. They don’t attack healthy cells. Known as phages, they are being researched as an alternative to antibiotics to treat conditions such as urinary tract infections (UTIs), acne, infected foot ulcers and tuberculosis.

This research has been driven by the rise in superbugs. Thanks to decades of blanket antibiotic use, increasing numbers of bacteria are mutating into lethal organisms resistant to our available medicines.

Given what we now know about viruses and how potentially lethal they can be, the idea of inhaling or swallowing one to treat an infection sounds like the last thing we would want to do

‘The potential for phage therapy is huge for anyone who has an antibiotic-resistant infection,’ says Joanne Santini, a professor of microbiology at University College London.

Indeed, in one remarkable story, in January doctors in Georgia reported on the success of phage therapy for a 30-year-old victim of the suicide bombing at Brussels Airport in 2016.

The patient, who’d undergone five operations, had been on antibiotics for nearly two years due to an infection in a wound in her thigh — it had become infected with a superbug, Klebsiella pneumoniae, and wouldn’t heal.

But within weeks of a phage being added to her medication, her broken thigh bone started to mend, and she can now walk and cycle, according to the journal Nature Communications.

The latest research also suggests phages may mean current antibiotics remain effective for longer. And a team of microbiologists has submitted plans to set up the first UK phage ‘bank’ to store phages, so they’re ready for other researchers and doctors to use when necessary.

You can help find wonder viruses — and even get one named after you

You can help discover potentially life-saving phages (viruses that kill bacteria) via the Citizen Phage Library. The aim is to build a database of phages so that if a patient needs treatment, there is a national resource that can offer this quickly, says Dr Ben Temperton, an associate professor of microbiology at the University of Exeter, who set up the project.

‘People are sent kits that contain three glass jars. They fill these with water from their local areas, such as ponds or rivers, and send them back to our lab. We filter out the bacteria and what’s left are viruses. We add these to a sample of bacteria we want to find phages for — if there are phages in the sample that kill the bacteria, they will increase in number.’ The phages are checked to ensure they don’t have any dangerous genes, then they’re added to the database. They are stored in liquid nitrogen, and if they’re needed, more will be cultured.

‘The low-cost process takes two to three weeks, in contrast to the time and money needed to develop new antibiotics,’ says Dr Temperton. ‘The citizen who sent it in can name the phage. My ten-year-old son was among the first to catch a phage — down the road from where we live in Devon, in the River Lemon. He named it LemonAid.’

LemonAid was found to infect and kill Acinetobacter baumannii, which the World Health Organisation lists as one of the drug-resistant bacteria that poses the greatest threat to human health. A phage named KylieMinegg was isolated from a chicken coop and killed Pseudomonas aeruginosa bacteria from cystic fibrosis patients, too.

The collection kits should be available within a month at citizenphage.com.

 

Phages — short for bacteriophage, meaning ‘bacteria eater’ — are found everywhere that bacteria exist, including in our bodies and the environment, such as soil or water. Phage therapy involves first identifying the bacteria that’s caused an infection, then finding a virus (i.e. the phage) known to kill that particular bug.

This is currently done by contacting phage researchers to see if they have anything that might help — but scientists worldwide are setting up online phage banks, where researchers log and share information about phages.

Once identified and sourced, these phages can be cultured in a lab and used to destroy the bacteria that is causing the disease.

What’s particularly promising is that, while phages can be used as a single treatment to target a specific bacteria, doctors can also develop phage ‘cocktails’ which contain a mix of phages for more complicated infections.

Phages can also be used alongside antibiotics to maximise the effect on the bacteria, because they work via different mechanisms.

‘If we combine phages with antibiotics, we attack the bacteria on two fronts and the bacteria struggle to become resistant to both,’ says Dr Ben Temperton, an associate professor of microbiology at the University of Exeter.

How phages work is partly down to their distinctive structure. Many have an icosahedron head — a bit like a die with 20 faces — which contains their DNA, on a tail that has leg-like fibres. These fibres bind to receptors on bacteria, and are different on every phage.

Once a phage binds to a bacterium, it injects its own DNA into it and hijacks the cell in order to replicate inside, until the bacterium reaches full capacity. At this point the cell bursts and dies, and the phages inside it are released into the body, where they continue to kill that bacteria. If they don’t find any, they simply die.

‘Because they are so targeted towards attacking one type of bacteria, phages are seen as a massive step towards personalised medicine for many diseases,’ says Martha Clokie, a professor of microbiology at the University of Leicester, who has researched phages for more than 20 years.

To widen access to phage therapy, last week Professor Clokie submitted plans to create the first UK phage centre, which involves creating physical banks of phages. While this is very much cutting-edge, strictly speaking, phages are not new — they were discovered just over 100 years ago at the Pasteur Institute in Paris.

Could they boost cancer treatment?

At Imperial College London, Amin Hajitou, a professor of targeted therapeutics, is taking a unique approach to bacteria-eating viruses, developing them into a delivery system to make treatment for brain cancer work better, and even cure genetic conditions.

‘For some chemotherapy medications, no more than 10 per cent will reach the tumour,’ he says. ‘We can’t simply increase the dose as they are toxic, so we must develop better delivery technologies.

‘A phage is ideal to develop into a delivery system since it doesn’t harm human tissue.

‘We know that cancer cells have specific markers for growth factors — we modified a phage so that it displayed “ligands” that bind to receptors for these growth factors. As soon as it binds, the phage enters into cancer cells.

‘The next step is to modify phage DNA so that when it gets into the tumour, it will produce a therapeutic protein that kills the cancer cell.

‘I expect to move this research into clinical trials in the next two or three years.

‘For genetic diseases, such as cystic fibrosis, the phage could deliver a gene that corrects a protein causing the disease, restoring normal function.’

 

But when scientists in the West created antibiotics in the 1940s, phages fell out of favour here. However, they continued to be developed in Eastern Europe. They are particularly popular in Georgia (the bombing victim’s phage came via the Eliava Institute in Tbilisi), Russia and Poland.

Phage therapy is so widely accepted in parts of Eastern Europe that not only are phages prescribed by doctors, you can also buy an off-the-shelf product from pharmacies, says Professor Clokie, who has worked in Georgia.

‘There is a pharmacy in the Eliava Institute where people queue around the block to buy little pots of phages which they swallow,’ she says. ‘These phages are prepared to respond to common strains of bacteria, and are effective against infections such as Klebsiella [found in wounds and pneumonia, for example], Staphylococcus [which affects skin] and E. coli [which affects the gut].’

Phage therapy is seen as a safe approach partly because phages are found naturally in our bodies, and form part of our gut microbiome — the community of microbes that play a key role in health.

While most people are familiar with the idea of ‘good’ and ‘bad’ gut bacteria, ‘we now understand that phages are an important part of that microbiome’, says Dr Temperton.

The phages in our guts are different from those that are being developed as treatments. As Dr Temperton explains: ‘Treatment with phages involves finding phages that are specialised to kill certain bacteria. These can often be found in the environment as they are different to those in the patient’s own microbiome, so the bacteria has not had the opportunity to develop resistance to them.

‘But from what we know about phages, they’re as safe as medicine can be, and certainly safer than many antibiotics in terms of side-effects.’

Phage therapy is so widely accepted in parts of Eastern Europe that not only are phages prescribed by doctors, you can also buy an off-the-shelf product from pharmacies, says Professor Clokie, who has worked in Georgia

Phage therapy is so widely accepted in parts of Eastern Europe that not only are phages prescribed by doctors, you can also buy an off-the-shelf product from pharmacies, says Professor Clokie, who has worked in Georgia

This is because unlike antibiotics, which kill both good and bad bacteria, a phage targets a specific type, so won’t disrupt the natural balance in our microbiome (or cause side-effects such as abdominal pain and nausea).

Professor Clokie suggests phages could be especially good for treating skin ulcers, lung infections and UTIs, as the phage can be targeted directly to the problem. This is because it’s relatively easy to identify the bacteria, and therefore the phage that suits them.

For instance, skin infections such as cellulitis are typically linked to staphylococcal infection.

‘Our studies suggest you can apply a Staphylococcus phage on the surface of ulcers, for instance, and stop deep infection that could lead to deadly sepsis or amputation,’ says Professor Clokie.

The main focus at this point, however, is tackling superbugs.

‘Because the problem of antibacterial resistance is so prominent there is a real risk that infections contracted from simple cuts or routine operations could become deadly,’ says Dr Antonia Sagona, an associate professor of infection and microbiology at the University of Warwick.

A recent study by the University of Oxford estimated that more than 1.2 million deaths worldwide in 2019 were a result of antibiotic-resistant bacterial infections, making them a leading cause of deaths now, reported The Lancet.

‘Increasingly, the only option for some people is to try phage therapy because all available medicines are ineffective,’ says Professor Clokie. ‘Sadly that isn’t possible in most cases in the UK as it isn’t approved, but we are seeing more interest from doctors who want to try phage therapy on compassionate use as a last resort.’

There have been a few early-stage phage clinical trials worldwide to date, which have produced mixed results. But there have been multiple case reports showing the success of phage therapy in clearing infections.

These include the only patient treated with personalised phage therapy in this country.

In 2019, Isabelle Carnell-Holdaway, then 15, developed a multi-drug-resistant Mycobacterium infection following a double lung transplant. Her doctors gave her a 1 per cent chance of survival and contacted U.S. specialists to search for a phage to save her.

Isabelle, from Kent, was given a three-phage cocktail. After six weeks there was a clear improvement in the infection, her doctors from Great Ormond Street Hospital in London reported in the journal Nature Medicine.

Phages are not a magic bullet — research suggests bacteria can become resistant to them, as with antibiotics, says Dr Temperton. But if this happens, phages are so diverse that you can ‘simply search for new ones or evolve the ones you have [e.g. through genetic engineering] to overcome the resistance’, he explains. ‘It’s much cheaper and faster [than looking for alternative antibiotics].’

Also, if phage resistance occurs, it could actually make the antibiotics effective against that infection once again, adds Dr Franklin Nobrega, a lecturer in microbiology at the University of Southampton.

In a 2020 study by Yale University in the U.S., E. coli bacteria (a common cause of food poisoning) resistant to antibiotics were mutated to be resistant to phages, too. The scientists found that in developing phage resistance, the bacteria had to change the structure of a protein (called TolC) that was key in making it resistant to antibiotics.

In effect, the phage resistance increased antibiotic sensitivity, according to the journal Proceedings of the National Academy of Sciences. ‘The upshot is that phage therapy seems to give us more options for treating serious resistant infections,’ says Dr Nobrega.

‘In any case, phages should not be used in the same blanket way that we have used antibiotics, as it could lead to resistance. They should complement the use of antibiotics and be used alone when antibiotics don’t work.’

Take a virus pill for a healthy gut 

Most people are familiar with the idea of ‘friendly’ bacteria in our gut being linked to wellbeing, and many now take probiotics to boost them.

But potentially as important are the ‘friendly’ viruses, suggests Martha Clokie, a professor of microbiology at the University of Leicester. These help keep disease-causing ‘bad’ microbes in line. ‘Within a decade it should be possible to get phages [‘good’ viruses that attack bacteria] over-the-counter just like any supplement,’ she says.

‘We know some groups such as children with asthma have less diversity in their phages, so they might benefit from a supplement to restore the natural balance of the microbiome [the colony of microbes that live in the gut].’

Joanne Santini, a professor of microbiology at University College London, adds: ‘The major advantage of phages is that you can use ones that specifically target and kill “bad” bacteria and do not directly harm our microbiome.

‘There’s no reason they couldn’t be used as a general supplement, much like probiotics, in future, to rebalance the microbiome and get rid of “bad” gut bacteria.’

 

Another key question is whether using a virus in this way triggers an immune response that causes harm or simply blocks the phage.

While studies suggest we release some antibodies in response to phages, there were no side-effects, says Amin Hajitou, a professor of targeted therapeutics at Imperial College London.

‘Also, the antibodies do not stop the phage performing its therapeutic effect, even if we repeat the phage treatment, meaning we can administer multiple doses quite safely.’

While there is a lot of research into phages being done around the world, the UK is at the forefront, says Dr Nobrega.

For example, Professor Clokie’s work has led to the groundbreaking discovery of phages (in soil within saltmarsh estuaries in Hampshire) that attack antibiotic-resistant strains of some particularly resilient superbugs, such as C. diff, a deadly bacterium commonly found in hospitals.

‘When I started some 20 years ago, most doctors questioned the validity of phage therapy, but now there is a lot of interest in it for many conditions,’ says Professor Clokie.

‘In my lab, we focus on the use of phages for recurrent UTIs and are planning clinical trials which are two to three years away. These will provide much-needed efficacy data and progress us to a point where phages can be used more routinely. There has also been very promising research for treating asthma.’

There is still so much to learn, but there is incredible promise. ‘Phages can potentially benefit anyone who has a resistant infection,’ says Professor Clokie. She, like Dr Sagona and others working in this field, often receive emails from people with infections who have run out of treatment options but may benefit from phages.

In the UK doctors can, under some strict conditions, apply to use personalised phage therapy that is approved in other parts of the world, as a last resort. Professor Clokie says: ‘We have started to consider using phages under compassionate use guidelines, but this has its challenges,’ referring to the lengthy approval process.

Dr Sagona believes that because ‘there are so many requests’ for phage therapy, ‘gradually there will be a change in regulations to make it more available’.

‘One of the goals of phage research in the UK is that, as well as targeted phage treatments, we will one day be able to buy phage cocktails from the pharmacy — as they do in Georgia,’ she adds.

‘Within a decade, and upon approval in the UK, phages can be available for patients as topical products, drinks or powder, targeting specific bacteria causing infectious diseases.

‘It could happen even faster, as phages in this format are already used safely in other countries. It depends solely on the Department of Health and governmental decisions, and not on the science; the science is already there.’

Professor Clokie adds: ‘Within a decade or so, if suitable funding is put into this research area, it will be plausible to get a phage product from a pharmacy for a general infection. Patients who have infections that don’t respond — or who have asthma or cystic fibrosis, for instance — may need a bespoke approach from a specialist.’

Phages may even help detect infection. At Dr Sagona’s laboratory in Warwick, they have genetically modified phages to produce luminescence (light) when they detect specific bacteria in a sample, such as blood, saliva or urine.

‘The plan is to develop this into diagnostic tests people can take at home. Currently recurrent bacterial infections are analysed by PCR test (or similar methods) and it can take a few days to get specific results,’ says Dr Sagona.

Phages are particularly useful here as they infect only live, disease-causing bacteria. PCR tests don’t distinguish between live and dead cells, which can lead to false positive results, she says. She and her team are working to create a universal test with enough sensitivity to detect common pathogens.

If this was the first time you’ve heard the term ‘phage’, clearly it will not be the last.

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