NOTEW YORK – At the end of 2020, Justin Frere, a nervous MD/Ph.D. student dressed head-to-toe in white Tyvek, took a clear pipette, methodically reached into the cages of 30 unsuspecting, sedated hamsters and dripped 1,000 infectious coronavirus particles into each of their nostrils.
Then he waited. Days for some. A whole month for the others.
Waiting was essential. His goal was to create a tool that experts say will be key to understanding and perhaps one day effectively treating long Covid, the debilitating and still poorly understood constellation of symptoms that plagues many Covid-19 patients long after the end of of their initial infection.
Frere and his adviser, New York University virologist Benjamin tenOever, were trying to make one of the first animal models for the long Covid. They reported the first results of the experiment this week in Science Translational Medicine, showing that hamsters mimic some symptoms and molecular changes seen in humans and pointing to several plausible explanations for the disease.
If further research confirms the findings, these hamsters and several other groups of animals from other labs could allow scientists to probe the basic biology of the mysterious disease, performing the kind of analyzes you could never do in the man. They can even allow academics and companies to screen therapies before testing them on humans, a crucial step in building what remains a sterile therapeutic arsenal.
“We urgently need new pathways to knowledge that can support diagnostics and therapies for this condition,” said Harlan Krumholz, a Yale cardiologist who has worked with long Covid patients and has not been involved in work, said in an email. “Any potential breakthrough, especially the development of an animal model, is welcome.”
TenOever is not alone. In December, a Yale lab reported test two possible therapies in a mouse model. The following month, scientists from Stanford and Yale presented a mouse model that shows the brain fog of both long Covid and cancer patients on chemotherapy live. Stanley Perlman, a coronavirus expert at the University of Iowa, told STAT he was working on his own model, using a version of the coronavirus adapted to infect mice.
Each of these models has different advantages and disadvantages – Yale mice, for example, had to receive some kind of gene therapy first before being infected with SARS-CoV-2, which could skew the results – but experts say the world will eventually need multiple animal models for long Covid.
This is because long Covid is probably not one condition, but an umbrella term for several separate conditions.
“We think our model recapitulates some aspects of the human long Covid, but I wouldn’t say it models the long Covid perfectly,” said Akiko Iwasaki, a Yale immunologist who helped create the Stanford-Yale model, in an email. “Long Covid is a very heterogeneous disease. There are probably four or five separate pilots. And, she said, “We need multiple models that reflect each.”
Right now, however, the simple fact that researchers can recreate some of the symptoms of long Covid in the lab is important as researchers continue to debate what caused the disease, said David Putrino, rehabilitation specialist at Mt. Sinai Health System who has been working with long Covid patients.
“Just saying the words ‘animal model of long Covid’ really explodes those claims that are meant to psychologize long Covid or tell people it’s just stress or anxiety,” Putrino said. , who contributed to Yale’s work.
At the start of the pandemic, tenOever used the hamsters in its Biosafety Level 3 lab – originally built for influenza research – to understand the course of the then-novel infection and possibly screen for drugs., at the request of the US government. But in late 2020, the advent of mRNA vaccines made such studies less urgent, at the same time as patient advocacy around the long Covid was bubbling and capturing the attention of researchers.
TenOever decided that their hamsters could also provide a good model for the long-term condition. They had already closely mimicked an acute infection in humans, likely because they have a similar type and levels of ACE2, the protein the coronavirus uses to embed itself in cells.
“Wherever we look, whatever we do with our hamsters, it’s always been phenocopied in humans,” he said. “You might find something interesting in the hamsters and then get a human biopsy sample that matched those and was still kept.”
This meant his team didn’t have to do what Perlman and Iwasaki did and modify the virus or modify the mouse for the model. They could just infect the hamsters and see what happens.
In addition to infecting 30 hamsters with Covid, Frere gave nothing to another 30 hamsters and infected another 30 hamsters with the virus from the 2009 swine flu pandemic. In theory, the twin controls would allow researchers to determine what changes were the result of any infection and what changes were unique to the coronavirus.
At first, some differences were clear: Covid hamsters that were examined after three days lost their sense of smell, unlike hamsters with the flu or not infected. Researchers showed this by placing hamsters in a new cage with buried Cocoa Krispies.
Flu and uninfected hamsters dug up the treats. Coronavirus hamsters would “kind of wander off and be like, why am I here?” says Brother.
There were, however, many similarities. The coronavirus and the flu triggered inflammation in the lungs and throughout the body, although the impact of the coronavirus was more severe.
And over time, the differences have narrowed. The coronavirus hamsters who were examined on day 31 – the time when symptoms can begin to be described as long Covid – could smell about as easily as the other two groups. None of the hamsters had viruses. The inflammation in much of the body was also gone, although there were some scars.
Except for one thing: the olfactory bulb, a fingerling potato-like mass of cells behind the nose that relays olfactory signals to the brain, remained inflamed even a month later.
“This is the only place where SARS-CoV-2 differs from your average response to infection,” tenOever said.
Although the olfactory bulb is not involved in cognitive functions, tenOever said, inflammation can radiate deeper into the brain. His group teamed up with a neurology lab and showed that many of the neurons in these hamsters still expressed genes associated with the body’s antiviral response.
They then examined the corpses of patients who had caught Covid-19 and died much later from unrelated causes, such as a car accident. Their brains showed a similar expression profile.
“They also had all their antiviral defenses, even though there was no virus there,” tenOever said.
This pointed to some possible explanations for the long Covid, as well as possible therapies.
Clearly, tenOever said, there is an overly potent inflammatory response against the virus, possibly because coronaviruses have a more stable and long-lasting genetic code than the flu. Although the body eventually eliminates it, the neurons could be permanently rewired.
There may also be remnants of RNA or other types of viral debris, including zombie-like particles called faulty viral genomes – the source of this inflammation, although the researchers have not found any.
Either way, you could test Paxlovid, Pfizer’s highly effective antiviral, either to clear the virus in newly infected patients and prevent long-term inflammation, or to clear potential viral debris in patients who have been suffering for a long time. long from Covid.
“It’s just the obvious choice, because it’s such a great drug,” said Ryan Langlois, an immunologist at the University of Minnesota who wasn’t involved in the work.
You can also test medications such as steroids that reduce inflammation or completely reset the immune response. Like Iwasaki’s group, tenOever suggested a treatment that eliminates the patient’s microglia, the brain’s guardian cells.
The work has impressed some doctors who have become specialists in the long Covid. “This model needs to be carefully considered”, Claire Stevea clinician from King’s College London, said in an email.
There are, however, important limitations. For one, the researchers only used the original coronavirus strain and not the variants currently in circulation, although tenOever points out that the experiments began more than a year ago and that many Covid patients long time have been infected with the original virus. They were also not really able to mimic most of the symptoms seen in patients.
The closest they got was a test where you put marbles in the cages. Stressed or anxious hamsters will immediately bury the marbles. Indeed, the long Covids did, but not at a considerably higher rate than the flu or the uninfected.
“Hamsters aren’t walking around with brain fog, heart issues, or developing diabetes,” said Perlman, the University of Iowa coronavirus expert. “Nothing great moment.”
Frere said they recognize this limitation. As well as testing treatments, if they can secure funding, they also hope to create models of hamsters that have pre-existing conditions such as heart disease or diabetes to see if they can better show the long full spectrum of Covid. . Current trials only involved healthy young hamsters.
They also hope to test other guesses about the long-standing origin of Covid, including a hypothesis – hinted vaguely in the data – that the virus can, by killing certain cells in the nose, alter the balance of the microbiome of a patient.
All of this, however, will require funding. And hamsters in a high-level containment facility don’t come cheap.
“These one-pop experiences are like 50,000,” tenOever said, referring to treatment studies. “It’s not a trivial amount of money.”
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