By Angus Dalton
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It started with an infection so bad Phoebe regularly blacked out.
“I wasn’t able to move, my heart rate was really high,” the 24-year-old from Melbourne, who was diagnosed with long COVID after a severe infection in February 2022, says.
Phoebe Kinrade spends half of her pay trying to manage her long COVID symptoms.Credit: Jason South
“Then I started getting all these new symptoms … fainting, fatigue, muscle aches, tremors, shaking, a lot of gut issues as well, nausea and vomiting, rashes. All of these things that really were unexplainable that I hadn’t experienced before.”
The most disturbing symptom: “I kind of had this feeling that it wasn’t necessarily going to get better.”
Long COVID has generated at least 24,000 scientific papers, making it one of the most-studied illnesses in history. But the exact causes of the life-altering condition are yet to be nailed down in a medically meaningful manner.
Phoebe had to halt her studies and cut down her hours as a mental health peer support worker. Now half of her pay goes towards affording medication and therapies: low-dose naltrexone for energy, antihistamines for new allergies, beta blockers for elevated heart rate, Botox for chronic migraines.
However, one of it addresses the root cause of long COVID because we still don’t know what that is. It’s a mystery that remains devastating for millions of people with the disease.
But in the search for better ways of stopping the illness, Australian scientists have zeroed in on a newly discovered chink in the virus’s armour.
Finding a new viral target
ANSTO’s Australian Synchrotron can accelerate a beam of electrons to almost the speed of light and produce light one million times brighter than the sun.
These super-tiny, super-bright “beamlines”, when fired at a molecule, can create a 3D snapshot of its structure. Professor David Komander, of Melbourne’s Walter and Eliza Hall Institute (WEHI), led a team of scientists in 2020 who used this method to identify the structure of a COVID-19 protein called PLpro.
Antibodies binding the SARS-CoV-2 virus.Credit: Dr Drew Berry/WEHI
PLpro is critical for a virus’s replication. It cleaves chains of amino acids into smaller foot soldiers that help the virus go on to infect more cells.
PLpro’s cousin, a protein called Mpro, executes a similar function. The antiviral Paxlovid inhibits Mpro, which helps prevent severe sickness.
But PLpro has another critical function: it suppresses Type I interferons, which are molecules crucial to a cell’s defence against viral attack. Inhibiting PLpro could, therefore, stop the virus replicating and block its ability to bamboozle our immune response.
After uncovering what PLpro looks like, scientists hunted through 400,000 chemical compounds at WEHI’s National Drug Discovery Centre to identify drug candidates that may block the protein’s function.
They found one that worked. And its potential to subdue the development of long COVID, they say, is unprecedented.
Blocking long COVID
Modelling a disease with more than 200 symptoms is difficult. But a COVID-19 mutation arose by chance in 2020 which allowed the virus to better infect mouse cells. That gave scientists the chance to replicate severe disease, and long COVID, within living animals from a real strain rather than one that was genetically engineered.
“We think it’s really one of the best models that closely mimics what you see in human long COVID patients,” WEHI’s Laboratory Head Dr Marcel Doerflinger says.
“There’s a lot of damage in the lung, persistent inflammation and infiltration of immune cells, fibrosis, issues in the heart, in the gastrointestinal tract. They have cognitive impairment, they have issues with anxiety and depression.”
When the scientists treated mice with the new PLpro-blocking compound at the acute phase of their infection – six hours for mice, equivalent to about three to five days into illness for a human – they could prevent severe disease better than Paxlovid could.
And the compound also did something Paxlovid can’t: it prevented the onset of long COVID symptoms. “That was something no one else had shown before,” says Doerflinger.
Doerflinger and his colleagues write in their new Nature Communications paper that the new compound may therefore be clinically relevant for the prevention and treatment of long COVID, although human studies are required to verify that claim.
“Any way to protect against long COVID is great,” infectious disease researcher Professor Kirsty Short from the University of Queensland, who wasn’t involved in the study, says.
“But perhaps the bigger question is, what do we do for people who are already living with long COVID?”
Could antivirals reverse, as well as stop, long COVID?
“The holy grail would be something to treat patients who have had long COVID already for a long time,” Doerflinger says. “I’m not sure this drug can do that.”
One leading theory of what causes long COVID holds that the disease is caused by reservoirs of the virus lurking and continuing to replicate within patients. Studies have reported prolonged viral shedding and COVID-19 RNA in people’s blood years after infection, lending support to the theory.
That’s why scientists are investigating whether antivirals can treat, rather than just prevent, long COVID. Two recent studies into Paxlovid, however, found it didn’t improve long COVID symptoms in patients prescribed short courses of the drug.
Another theory, Short says, is that long COVID is caused by fragments of the virus persisting in the body that spark up inflammation. If that’s the case, antivirals mightn’t help. The disease may also be caused by an imbalance in the gut microbiome or a haywire inflammatory immune response, or some combination of these theories.
Short is one of the scientists behind a long COVID risk calculator. Running it for yourself can be pretty shocking – according to the calculator I had a greater than 50 per cent chance of at least one symptom hanging around after my next infection.
Many of us might have moved on from worrying about COVID, but the risk of life-altering effects from your next bout of illness remains real, Short says.
“This is a disease where we have no diagnosis, no treatment, no cure. And we really need to fix that.”
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