For most people, norovirus causes a few days of bathroom misery, then is quickly forgotten. Epstein-Barr virus can pass without any indication. And many people are ignoring COVID-19.
But a growing body of research suggests that in an unfortunate few, the immune system overreacts to these seemingly minor insults, leaving symptoms for years or even a lifetime.
“The wrong genetics with the wrong infection at the wrong time,” explained Dr. Judith James, a rheumatologist and vice president of clinical affairs at the Oklahoma Medical Research Foundation. “I think we have a growing body of evidence that means people should have this on their radar.”
It has long been suspected that seemingly simple infections can leave a lasting mark.
New research has found a possible link between a bout of norovirus, commonly known as stomach flu, and Crohn’s disease, a long-term inflammatory bowel condition.
Other recent studies have blamed Epstein-Barr infection for later multiple sclerosis.
And about 10% to 30% of people infected with COVID-19 have symptoms that last for months to years.
Typically, the trigger occurs when a bug or drug appears to the immune system as one’s own cells or tissues, said Dr. Raymond Chung, a liver specialist at Massachusetts General Hospital and Harvard Medical School. This mimicry provokes a response, and then the response perpetuates the problem.
Understanding how this cycle begins and then intensifies could lead to treatments, Chung said.
“If we can really catalog these steps, then I think we would be in a better position to think about interrupting the cascade,” he said. Careful recruitment of the response will be key, he said, because broadly blocking the immune response “could have unintended consequences.”
Even if people can’t avoid everyday pathogens, it’s important to identify the links between them and the long-term consequences, Chung said.
“Knowledge is power,” he said. “We really need to understand our own predispositions to these kinds of exaggerated, abnormal responses – but that will take time.”
Short illness, long misery
For decades, researchers have believed that infections and insults can lead to long-term problems.
Chickenpox has been known to reappear later in life as herpes zoster, an extremely painful nerve disease. The 1918 flu caused some people to develop Parkinson’s disease. Human papillomavirus infection can lead to cancer years later. And for a long time it was thought that chronic fatigue syndrome must be the result of some kind of infection.
But solid scientific evidence has only been accumulating in recent years, said Mark Davis, who directs Stanford’s Institute for Immunity, Transplantation and Infection.
Mapping both the human and mouse genomes has helped researchers understand the role of immune system genes at a deeper level, he said.
The norovirus study used a mouse with the same genetic mutation often associated with intestinal disease. When infected with norovirus, the mouse’s immune system produced T cells that damaged the gut as expected. But it also prevented the T cells from releasing a protective factor that would otherwise repair the gut. So the mouse is less able to recover from the infection.
Although it is difficult to prove that the same thing happens in humans, the study provides a plausible explanation for this link between infection and disease, said the paper’s lead author, Ken Cadwell, who studies how viruses interact with the immune system at New York University’s Grossman Faculty of Medicine.
By itself, stomach disease is usually “minor,” said Dr. John Wherry, who directs the Institute of Immunology at the University of Pennsylvania Perelman School of Medicine. A number of people have a genetic mutation that itself is just as minor. But when someone with a seemingly minor mutation gets a seemingly minor infection, it can upset the balance of the insects that live in their gut, leading to intestinal disease.
It was difficult to prove this sequence of events because the virus was gone by the time symptoms appeared. Researchers had known that the balance of gut microbes was disrupted, but until this new study, the trigger had not been shown to be a simple infection, he said.
“It’s a trifecta,” Wherry said. “It’s like a real ecosystem.”
Why are some people more vulnerable?
Genetics is a key factor in this cascade of diseases.
But figuring out which genes cause vulnerability to which infections is no easy task.
“There are many diseases, and each one will have a different set of molecules at play,” Davis said.
Overall, about 1 in 12 people will develop an autoimmune condition in their lifetime, James said.
Young adult women are known to be particularly vulnerable to autoimmune diseases, although no one knows exactly why.
“Women often have a slightly stronger immune response, and it’s more noticeable during these childbearing ages,” she said. Hormones may play a role, but they don’t fully explain the difference. “We don’t have all the answers.”
Anyone with an autoimmune disease in the family has a higher risk of developing an autoimmune disease, James said. However, identical twins may or may not get an autoimmune disease if their co-twin does, or they may develop it decades later. Autoimmune diseases can also be ‘sporadic’, occurring with no apparent family connection.
Siblings of children with type 1 diabetes are known to be at higher risk of the disease. So efforts are underway to understand their shared genetics and track changes in siblings’ immune systems “before the disease even develops,” James said.
Because these conditions rarely start at birth, there’s probably some tipping point that happens later in life, such as an infection, James said: “Maybe you need either a lot of genetics and a little infection, or a lot of infection and some from genetics.”
Instead of labeling most people as high-risk, it may be easier to quickly tell when someone’s immune system is overreacting to an insult like an infection, she said.
“Can we just push it back a little bit,” or progression of prevention, she wonders.
While these long-term symptoms may be something individual “between a particular mistake, a particular person and perhaps a particular point in time,” there are common mechanisms in these conditions, Davis said. Hopefully, this means scientists will eventually learn how to use these mechanisms to develop treatments.
“It’s becoming increasingly clear how these diseases started,” Davis said. “What is not clear is why they persist in certain people. Why doesn’t the system return to balance again?’
Finding that and curing the disease, “that’s the next chapter in all of this,” he said.
Can you defend yourself?
Davis is desperate to develop a test that identifies a struggling immune system the way a cholesterol test indicates brewing heart problems.
“As an immunologist, I feel uncomfortable,” there isn’t one, he said.
Davis scoffs at commercial “immunostimulators,” saying that at best they’re just separating people from their money, and at worst they can be harmful.
Living in a bubble is not the answer, Chung said. In recent years, research has shown, for example, that overprotecting children by avoiding allergens at an early age can actually increase the risk of allergies later in life.
What’s really needed is for researchers to understand what makes someone more vulnerable to the long-term consequences of infections, Chung said: “Part of it is genetics. But part of that might also be understanding what your immune profile might be at any given time in Then we can ask, is that problematic? Is this a sign of risk?”
A healthy lifestyle — getting enough sleep, avoiding cigarettes and too much alcohol, and a healthy diet — are important for protecting the immune system, James and others said.
Accumulating evidence suggests that the microbiome—the microorganisms that live on and in everyone’s body—can influence the immune system. But it’s still too early to know what can be done to boost immune health through the microbiome, James said.
Although there’s not much people can do to understand their own risk, researchers say there’s no point in panicking.
“I’m not one to get hysterical about these things,” Wherry said. “Infections and germs are part of our world, part of our life, part of our lives.”
Instead, it makes sense to make simple behavioral changes like washing your hands frequently, wearing a mask at a busy airport and staying home instead of fighting off an illness, he said.
“If you know everyone in your friend’s family has been sick for the past week and they invite you over for dinner,” he said, “maybe do a rain check next week.”
The study compared antibody responses in the blood serum of patients recovered from COVID-19
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