Brent Palmer’s first inkling of Long COVID began in the early days of the pandemic, before the term “Long COVID” even existed.
Some of his friends had contracted the virus during a ski trip and returned to Colorado with the mysterious new disease. It was a scary time — and an irresistible opportunity for Palmer, who studies the immune response to infectious diseases like HIV.
In particular, he was curious to see how their T cells, part of the immune system’s arsenal to fight infection, deal with the novel infection. So he started taking blood samples from them. And there was one topic that particularly fascinated him. More than six weeks after her acute illness, she was still struggling with heart palpitations, chest pains and breathing difficulties.
In the lab, Palmer noticed that she still had a very high percentage of these anti-virus T cells compared to her husband, who had also fallen ill but had no lingering symptoms. “They reacted very differently,” says Palmer, an associate professor of medicine at the University of Colorado.
Typically, T cells that target the virus peak during acute infection and fall off over time, but Palmer noted that wasn’t the case when he began studying more patients with these persistent symptoms .
“These individuals had, in some cases, a 100-fold higher frequency than those who had no ongoing symptoms,” he says.
In fact, Palmer says it’s like her body is still fighting the virus. It got him asking: “Despite the fact that they test negative in a nasal swab, does the virus still persist in the lungs? Is it in another organ?”
Other scientists trying to uncover the roots of the long COVID have asked a version of the same question in recent years. This “viral persistence” theory posits that some people never completely clear the infection, virus reservoirs persist in the body, potentially triggering the symptoms of a long COVID.
Although a direct link has not yet been proven, this line of research has gained momentum as more evidence has surfaced that some people appear to harbor “reservoirs of the virus” after their original illness has passed. This is far from the only explanation being considered. but some scientists see it as one of the most promising.
“There is enough evidence to point to virus reservoirs as a leading driver of long COVID,” says microbiologist Amy Proal, president of the PolyBio Research Foundation, which spearheads research into virus persistence.
A reservoir… but where?
Much of the research related to virus persistence comes from two sources: evidence that the virus persists in different parts of the body, and evidence that some people’s immune systems are still ramping up months after the acute illness.
For example, Palmer and his team eventually found that patients with long-lasting COVID had higher frequencies of virus-specific T cells than those who had no ongoing symptoms — and this was also associated with higher levels of systemic inflammation, poorer lung function, and longer duration of symptoms such as cough and difficulty breathing. Other teams have made similar observations about the sustained immune response in long COVID patients.
Then there are all the corners of the body where scientists have discovered that genetic material or proteins of the virus appear to linger. Patients with persistent symptoms have traces of the virus in their stools many months after infection, while tissue samples from the gut also showed evidence of virus persistence. In other reports, biopsies taken from different parts of the body have led to similar conclusions that parts of the virus can be recovered many months later in some patients.
A thorough autopsy study published late last year has also substantiated the case for virus persistence.
By studying people who died after a case of COVID-19, Dr. Daniel Chertow found evidence of the “virus in over 30 different cell types” and “in tissues throughout the body and all major organs”.
In one case, genetic material from the virus was present in a person who died more than 200 days after contracting COVID-19. In another, Chertow and his team were able to culture viruses from tissue samples taken from the brain of a person who died within two weeks of becoming ill.
“It provides definitive evidence that the virus can spread throughout the body and persist in parts of the body,” says Chertow, who is a researcher at the NIH Clinical Center and the National Institute of Allergy and Infectious Diseases.
Chertow warns that there is only so much that can be extrapolated from the study because of its long lack of specific screening of COVID patients. The subjects were also typically older and had underlying health conditions — a very different population from those with long-COVID who were healthy and had a mild case of COVID-19 before developing chronic symptoms.
“Ultimately, the role of viral persistence in causing or contributing to the clinical symptoms and signs that people with long experience of COVID have has yet to be determined,” he says, “but our paper offers strong biological plausibility that it is.” can contribute to this.”
Unanswered questions
All of this research has brought new attention to the concept of viral persistence after an acute illness, says Dr. Michael Peluso, an infectious disease specialist at the University of California, San Francisco, who has long studied COVID.
He notes that this was a “game changer” in our understanding of Ebola after researchers realized that survivors of the disease might harbor virus reservoirs in parts of the body that were difficult for the immune system to reach. However, Peluso emphasizes that there are still important research gaps regarding long-term COVID. For one, the evidence of virus persistence comes from people with persistent symptoms and others who don’t.
“It seems that we can recover particles of this virus in at least some people for much longer than we initially expected,” says Peluso. “It is not yet clear whether there is a direct correlation between these measurements and the person’s clinical condition.”
Mohamed Abdel-Mohsen — an associate professor at the Wistar Institute’s Vaccine and Immunotherapy Center — echoes that sentiment, saying there is now “overwhelming evidence” of a viral reservoir in some individuals, but to what “degree this relates to the mechanism.” or contributes to the symptoms of long COVID” remains to be seen.
More than one cause. How are they related?
If there’s any consensus, though, it’s that researchers don’t think viral persistence will serve as that only Explanation for all who suffer from it.
“No one thinks the exact same thing happens with every long COVID patient,” says Proal.
And other possible mechanisms are being considered. These include but are not limited to autoimmunity and other immune system problems, tiny blood clots and inflammation of the lining of blood vessels, tissue damage, the reactivation of dormant viruses, and signal problems with the brainstem and vagus nerve.
“Right now we have these buckets,” says Peluso. “Ultimately we need to connect all the dots and see how these different mechanisms are related and whether certain pathways are related to certain subsets of symptoms,” he says.
An additional challenge is that the definition of long COVID varies significantly from study to study. And while researchers have identified distinct clusters of symptoms, the diagnosis can still serve as a sort of catch-all for myriad post-COVID-19 issues, making it all the more difficult to investigate.
Even the relatively simple term “virus reservoir” can obscure an unsolved mystery. What actually remains?
There are many definitions of a reservoir, but there’s still no evidence that people with long COVID “actively replicate infectious viruses that can spread to others,” Peluso says. “For me something [reservoir] That said, there are at least parts of the virus, even if they’re not infectious, that alter people’s immune responses after infection and potentially contribute to their symptoms,” he says.
Proal’s foundation recently helped launch a series of studies using advanced imaging and tissue biopsies to create a more accurate picture of these reservoirs.
It’s possible that the virus’ “genetic backbone” produces viral proteins in specific tissues — the most likely sites being the gut, lungs and nerves — which then enter the bloodstream, says Proal. The reservoir could look different depending on where it is located, replicating and making proteins at certain times and being inactive at others.
“There are all sorts of possibilities and nuances,” she says. “Does it stop in certain parts of the body more than others? If it stops in one part of the body, does it have a different mechanism for staying there?
Not mutually exclusive
Viral persistence is an attractive direction for long-term COVID research as it may be compatible with other leading theories on disease pathophysiology.
“These could actually all converge and come together in a coherent manner, so they’re not necessarily mutually exclusive,” says Dr. Linda Geng, co-director of Stanford University’s long-running COVID clinic.
A viral reservoir can wreak havoc on the immune system in a variety of ways. “A chronic reaction to something could lead to immune dysfunction and inflammation,” says Abdel-Mohsen.
Palmer, for example, notes that T cells produce small proteins called cytokines that can trigger inflammatory responses that “are not good for your body over long periods of time.”
Virus reservoirs could also trigger the microclotting phenomenon seen in some patients and neurological symptoms via the vagus nerve, which runs throughout the body and can relay inflammatory signals to the brain, Proal says. “This can activate brain cells that drive neuroinflammation and cognitive problems.”
At the Wistar Institute, Abdel-Mohsen has found evidence that fungi, which should be in the lungs and intestines, enter the bloodstream in some people with long COVID.
“This can lead to chronic inflammation,” which then alters immune cells to produce metabolites with neurotoxic properties.” And it’s possible that virus reservoirs hiding in the gut are helping trigger this “vicious cycle” that’s going on with local inflammation and damage, the intestinal barrier begins.
While all of these theories need to be carefully examined, Abdel-Mohsen says that in many cases “each could occur independently and lead to a problem, but they can also lead to each other.”
“There are still many unanswered questions, and many of the studies are smaller studies,” says Geng, who is leading a clinical trial to test whether a 15-day course of the antiviral Paxlovid helps long COVID patients.
The results are expected later this year. If it works, that would indicate that the drug has wiped out an ongoing infection.
“There are still many people who are suffering and we really need to be able to find answers for them,” says Geng.
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