For most people, norovirus causes a few days of bathroom misery and is quickly forgotten. Epstein-Barr virus can pass without any symptoms. And many people are shrugging off COVID-19.

But a growing body of research shows that in some unlucky ones, 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 more and more evidence that people should see this on their radar.”

It has long been suspected that seemingly simple infections can leave a lasting mark.

A new study has found a likely link between a bout of norovirus, better known as stomach bacteria, and Crohn’s disease, a chronic inflammatory bowel disease.

Other recent studies have blamed Epstein-Barr infection for later-onset multiple sclerosis.

And 10% to 30% of people who contract COVID-19 have symptoms that last months to years.

Typically, the trigger occurs when a disease or drug treats the immune system as its own cells or tissues, said Dr. Raymond Chang, a liver specialist at Massachusetts General Hospital and Harvard Medical School. This mimicry incites a reaction, and then it perpetuates the problem.

Understanding how this cycle starts and then escalates could lead to treatments, Chang said.

“If we could actually catalog these steps, I think we would be in a better position to think about interrupting the cascade,” he said. He said that carefully reducing the response will be key because broadly blocking the immune response “can lead to unintended consequences.”

Even if people can’t avoid everyday pathogens, it’s important to determine the link between them and long-term consequences, Chung said.

“Knowledge is power,” he said. “We really need to understand our own propensity for these kinds of exaggerated, dismissive responses, but that will take time.”

Short illness, long suffering

For decades, researchers believed that infections and insults could lead to long-term problems.

Chickenpox is known to reappear later in life as shingles, an extremely painful nervous disorder. The 1918 flu caused some people to develop Parkinson’s disease. Infection with human papillomavirus can lead to cancer years later. And for a long time it was believed that chronic fatigue syndrome should be the result of some kind of infection.

But hard scientific evidence has only been accumulating in recent years, said Mark Davis, who directs Stanford’s Institute for Immunity, Transplantation and Infection.

Mapping 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 that received the same genetic mutation often associated with intestinal disease. When infected with norovirus, the mouse’s immune system produced T cells that, as expected, damaged the intestines. But it also prevented the T cells from releasing a protective factor that would otherwise repair the gut. Therefore, the mouse was less able to recover from the infection.

​​​​​​While 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 senior author Ken Cadwell, who studies how viruses interact with the immune system, with the New -York University Grossman. School of medicine.

by itself stomach bug usually “insignificant,” said Dr. John Ware, who directs the Institute of Immunology at the Perelman School of Medicine at the University of Pennsylvania. A certain number of people have a genetic mutation that is equally insignificant in itself. But when a person with a seemingly insignificant mutation gets a seemingly insignificant infection, it can upset the balance of bugs living in their gut, leading to intestinal disease.

It was difficult to prove this sequence of events because the virus had disappeared by the time symptoms appeared. Researchers know that the microbial balance in the gut has been disrupted, but until this new study, it had not been shown that a simple infection was the cause, he said.

“It’s a trifecta combination,” Ware said. “It’s like a real ecosystem.”

Why are some people more vulnerable?

Genetics is a key factor in this cascade of diseases.

But finding out which genes cause vulnerability to which infections is not an easy task.

“There are many diseases, and each one will have a different set of molecules at play,” Davis said.

In general, about 1 in 12 people will develop an autoimmune condition throughout their lives, James said.

Young adult women are known to be particularly vulnerable to autoimmune diseases, although no one knows exactly why.

“Women often have a stronger immune response, and it’s more noticeable in childbearing age,” 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 autoimmune disease, James said. Identical twins, however, may or may not develop the autoimmune disease when their co-twin has it, or it may develop decades later. Autoimmune diseases can also be “sporadic”, occurring without an obvious family link.

Siblings of children with type 1 diabetes are known to be at greater risk of the disease themselves. So efforts are being made to understand their shared genetics and track changes in siblings’ immune systems “before the disease even develops,” James said.

Because these diseases 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 genetics.”

Instead of identifying most people as high-risk, she said, it would be easier to quickly spot when someone’s immune system is overreacting to an insult, such as an infection.

“Can we just push it back a little bit” or prevent progression, she wonders.

While these long-term symptoms can be an individual thing “between a particular bug, a particular person and perhaps at a particular point in time,” there are common mechanisms in these conditions, Davis said. Hopefully, this means that scientists will eventually learn how to use these mechanisms to develop treatments.

“It’s becoming more and more clear how these diseases arose,” Davis said. “The only thing that is unclear is why they are stored in certain people. Why doesn’t the system return to equilibrium again?’

Figuring that out and treating the disease “is the next chapter in all of this,” he said.

Can you protect yourself?

Davis is desperate to develop a test that detects problems with the immune system, the way a cholesterol test indicates brewing heart problems.

“As an immunologist, I feel embarrassed,” he said.

Davis scoffs at commercial “immune boosters,” 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 solution, Chang 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 a person more vulnerable to the long-term effects of infections, Chung said: “Part of it is genetics. But part of it may also be understanding what your immune profile might be at any point in time. Then we can ask, is this a problem? is this a risk sign?”

A healthy lifestyle– get enough sleep, avoid cigarettes and too much alcohol, and eat food healthy food— all of which are important for protecting the immune system, James and others said.

A growing body of evidence suggests that the microbiome — the bugs that live on everyone’s body — can influence immune system. But it’s too early to know what can be done to boost immunity through the microbiome, James said.

While there’s little people can do to understand their own risk, researchers say there’s no point in panicking.

“I’m not one to get hysterical about it,” Ware said. “Infections and germs are part of our world, part of our lives, part of life.”

Instead, it makes sense to make simple behavioral changes, such as washing your hands often, wearing a mask at a busy airport and staying home rather than contracting the disease, he said.

“If you know everyone in your friend’s family was sick last week and they invite you over for dinner,” he said, “maybe check the rain next week.”

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