Infection connections

For most of human existence, getting sick has meant getting infected by a microbe. A viral, bacterial, fungal or parasitic infection was the chief reason many — if not most — kids didn’t survive childhood, much less grow up to have kids of their own. Evolution has shaped our immune system accordingly, priming it to fight off infectious disease and keep us alive into adulthood and not worrying too much about things that happened after we succeeded in warding off the acute effects of microscopic pests and pestilences.

Yes. We still catch colds, flus, COVID-19 and other diseases caused by infectious microbes. But by and large, the torch of health problems has been passed to chronic diseases — neurodegenerative disorders, autoimmune diseases, cardiovascular troubles, cancer and more — that crop up as we reach childbearing age and beyond.

Gathering evidence indicates that some of these conditions may owe their existence to earlier acute microbial infections. The causal connections aren’t always obvious, because the acute infectious episode and the chronic sequel may be separated by decades.

If we knew which infectious microbes cause, or contribute to, which chronic diseases (still mostly a big if), we might know when and how to intervene before the one gives rise to the other. After all, it’s got to be a heck of a lot easier to cure or prevent an infection than to undo, decades later, the damage to our organs and tissues that infection set in motion. It would be like handing Humpty Dumpty a seat belt before the fall.

Here are some stories of how Stanford Medicine investigators, among others, have pieced together disparate clumps of evidence to tie acute infections to chronic conditions.

Influenza and Parkinson’s disease

Say what you like about the COVID-19 pandemic of recent years, the influenza pandemic that swept the world in and around 1918 was arguably far worse. That virus infected one-third of the globe’s population, killing 50 million people. In a single year in the United States, the pandemic knocked 12 years off people’s life expectancy.

Strangely, said Victor Henderson, MD, a professor of epidemiology and population health and of neurology and neurological sciences, “a number of recovered pandemic-flu patients developed a movement disorder that looked a lot like Parkinson’s disease.”

The experience of the 1918 pandemic made flu infection a prime suspect.

So, Henderson and colleagues at Stanford Medicine, Harvard Medical School and Aarhus University Hospital in Denmark looked into it. Denmark’s national health service maintains scrupulous records of that country’s population, including data on patients’ doctor visits, physicians’ diagnoses and hospital stays.

The investigators probed 61,626 patients’ records for any links between an influenza infection and a later diagnosis of Parkinson’s. They knew that 10,271 of the patients they selected had eventually received Parkinson’s diagnoses.

“A number of recovered pandemic-flu patients developed a movement disorder that looked a lot like Parkinson’s disease.”

Victor Henderson, a professor of epidemiology and population health and of neurology and neurological sciences

Henderson and his associates found, in a study published in 2021 in JAMA Neurology, that an influenza diagnosis equated with a 70% increase in risk for Parkinson’s disease 10 or more years down the road. By 14 years after a flu diagnosis, that risk increase had risen to 90%.

“The risk was specific for influenza, not any other infectious disease, and this increased risk showed up only a decade or more after the viral infection,” Henderson noted. “That makes sense, because Parkinson’s disease takes a long time to manifest. You wouldn’t expect it to be caused by an illness that occurred just a few months or a couple of years ago.”

Why the connection? That’s far from clear, although Henderson said that the flu typically triggers systemic inflammation (that’s what makes you feel rotten), which has been implicated in numerous chronic diseases.

Flu is no fun. Parkinson’s disease is worse. Might getting vaccinated for seasonal influenza help stave off Parkinson’s? That’s an open question, difficult to answer definitively, Henderson said, because to set up a credible observational study, “you’d need a country with a large group of unvaccinated people and with great health records.” That combination doesn’t come along often. But sometimes, it does.

Shingles and dementia

A quirky decision by another national public-health authority, this time Welsh, enabled Pascal Geldsetzer, MD, PhD, an assistant professor of primary care and population health, to show that getting vaccinated against shingles protects people against dementia.

In 2022, Geldsetzer began to take a hard look at the results of a 2013 national shingles-vaccination rollout in Wales. He got hold of a detailed database kept by the Welsh government, which had decided to make the then-dominant shingles vaccine, Zostavax, available for free to all citizens age 70 and older who hadn’t turned 80 by Sept. 1 of that year. Anyone born more than 80 years before that date, even by one day, was out of luck — they’d have to spend their own money to get the vaccine.

“They were ineligible for life for a free shot,” Geldsetzer said. “It was a raw deal for them. They could still go out and pay for one, but very few did.”

Geldsetzer zeroed in on the many hundreds of people born just before, or just after, the cutoff date. These 80-year-olds were virtually indistinguishable in every way except for being a week or two apart in age — and, obviously, in their probability of being vaccinated against shingles.

“They were all alike, except for that,” Geldsetzer said. “They had everything in common but their birth dates. Here we had this beautiful natural experiment — a scenario in which we have randomization just as would happen in a clinical trial, but done by nature, not by the investigator.”

The scientists followed those two groups for up to eight years and showed that the vaccine clearly reduced shingles incidence — no surprise, given that clinical trials of Zostavax had shown reductions of around 60% over five years.

More interesting was another result: Vaccination had a pronounced protective effect on the incidence of dementia.

“Our findings strongly implied that 1 in 5 new dementia diagnoses among unvaccinated people could have been averted by vaccination,” Geldsetzer said. “If these are truly causal effects, then getting vaccinated for shingles is far more effective, far less risky and much less expensive than anything else out there now for dementia.”

“If these are truly causal effects, then getting vaccinated for shingles is far more effective, far less risky and much less expensive than anything else out there now for dementia.”

Pascal Geldsetzer, MD, PhD, an assistant professor of primary care and population health,

Geldsetzer’s findings were published in Nature in 2025. He and his colleagues have since seen similar results in studies conducted in several other countries where arbitrary age cutoffs were imposed on shingles-vaccine eligibility.

What does getting vaccinated for shingles have to do with preventing dementia in the first place? That’s not certain, but there are hints.

The virus responsible for causing shingles, varicella zoster virus or VZV, is the same one that causes chickenpox. It used to be that everyone got chickenpox, an immensely contagious disease, in childhood. Since the advent of a vaccine, routinely administered to kids in the United States since the 1990s, not many do.

VZV is a member of the herpesvirus family, some of whose members are neurotropic: They preferentially target the nervous system. After causing a bout of chickenpox, VZV hibernates in our sensory nerves for the rest of our lives.

“The virus plays hide-and-seek with the immune system,” Geldsetzer said. As we age and our immune surveillance weakens, the dormant virus can reactivate and make its way down our sensory tracts to the nerve endings at the surface of the skin, where it pops out and brings on the painful patchy rash we call shingles.

A link between neurotropic viruses and dementia diagnoses has been known for a while, Geldsetzer said. But it took a massive natural experiment to convincingly nail down VZV, in particular, as a culprit.

It’s smart to get vaccinated for shingles, Geldsetzer said.

But how about younger people who’ve been vaccinated for chickenpox? “They could still be infected,” Geldsetzer said, “About 15% of vaccinated people still do get chickenpox, although it’s typically only a mild case. Besides, if the protection is due to some still-unknown broader mechanism — say, a vaccination-induced boost to the immune system that’s independent of viral infection, then it doesn’t matter whether you carry VZV or not.”

Another question: Was it prevention of herpes or the generation of an immune response to Zostavax that was performing the protective trick?

“We don’t know,” Geldsetzer said. That matters, because there’s a new kid on the block: Shingrix, a shingles vaccine introduced in 2017. Shingrix, whose composition is substantially different from Zostavax’s, might prove even more protective against dementia than Zostavax was, Geldsetzer said, because it’s more effective than Zostavax was in reducing viral reactivation — by upward of 90%, in clinical trials leading to its approval.

Or it might not.

Geldsetzer is seeking funding from private foundations and philanthropy to start a clinical trial to find out. He also intends to extend his previous studies’ findings by incorporating cognitive-performance tests rather than simply settling for dementia diagnoses. And he wants to unravel the precise mechanism by which shingles vaccination protects people from dementia.

Epstein-Barr virus and multiple sclerosis

Another herpesvirus, Epstein-Barr virus, or EBV, has been tied to a different neurological condition: multiple sclerosis.

About 1 million people in the United States and 3 million globally (nearly three-fourths of them women) have this autoimmune disease.

Our immune system attacks cells and proteins it deems suspicious: belonging, perhaps, to a bacterial or viral pest. Blessedly, the immune system has been trained in early fetal and childhood development to recognize our own proteins as perfectly normal and to be nice to them.

But that peace treaty isn’t perfect. Now and then, the immune system becomes sensitized to a “self” protein toward which it should show forbearance and becomes angry instead. That’s what’s called autoimmunity.

Multiple sclerosis is but one of more than 100 identified autoimmune disorders. In this disorder, the immune system attacks brain cells called oligodendrocytes, whose job is to wrap our neurons in fatty coatings that insulate neurons electrically and vastly speed up signal transmission in the brain.

The attacks leave patches of “bare wire” on random neurons, resulting in a grab bag of defective circuits — symptoms depend on where the destruction occurred — that, while varying from patient to patient in their exact location in the brain, are uniformly the hallmarks of multiple sclerosis.

Some 20 or more studies have provided epidemiological evidence suggesting a link between EBV and multiple sclerosis, said Tobias Lanz, MD, assistant professor of medicine at Stanford’s Institute for Immunity, Transplantation and Infection and in immunology and rheumatology. Virtually 100% of multiple sclerosis patients were infected with EBV before they were diagnosed with MS.

But that’s not definitive proof, Lanz said. Understanding the evidence he and his colleagues unearthed requires an excursion into the land where virology meets immunology.

“We knew that myelin — the fatty material oligodendrocytes lay down on nerve cells to insulate them — is the immune system’s target. But we didn’t know which protein constituents of myelin get mistakenly targeted by our immune system.”

Tobias Lanz, MD, an assistant professor of medicine at Stanford’s Institute for Immunity, Transplantation and Infection and in immunology and rheumatology

EBV, one of nature’s most successful viruses, is living the dream. No vaccine is yet available, and the vast majority of us humans are infected by EBV by the time we reach age 25. While typically asymptomatic, the infection can trigger an acute condition called mononucleosis (also known as “the kissing disease” because it’s most commonly transferred through saliva). Symptoms — including fever, sore throat, severe fatigue, swollen lymph nodes and feeling rotten — can last for weeks before fading away.

The Epstein-Barr infection itself, though, is a life sentence because the virus uses our cells as safety-deposit boxes for its genes, which are the recipes for its proteins. More than 95% of the human population, however otherwise healthy, is carrying EBV’s dormant genetic material inside their B cells (the antibody-producing cells of the immune system) and salivary glands — without ever becoming too sick to continue transmitting the virus to others.

Lanz was the lead author of a 2022 paper in Nature that pieced together an explanation of why an Epstein-Barr infection is a necessary prelude to multiple sclerosis. He worked with colleagues including Stanford Medicine faculty members William Robinson, MD, PhD, the James W. Raitt, MD, Professor and professor of immunology and rheumatology; Lawrence Steinman, MD, the George A. Zimmermann Professor and professor of pediatrics and of neurology and neurological sciences; and Chris Garcia, PhD, the Younger Family Professor and professor of molecular and cellular physiology.

In 2015, Lanz was a postdoc in Robinson’s lab. The team was wondering which proteins in the body had features that could confuse the immune system into revving up and causing multiple sclerosis. If they could find the culprit, they reasoned, it might be possible to find some way to prevent this confusion and treat or prevent the autoimmune disorder.

“We knew that myelin — the fatty material oligodendrocytes lay down on nerve cells to insulate them — is the immune system’s target,” Lanz said. “But we didn’t know which protein constituents of myelin get mistakenly targeted by our immune system.”

He and his teammates had a hunch, though. As EBV hides out forever in people’s immune cells over the decades, just one of its 80 or so proteins, called EBNA1, continues to be produced by the cells harboring that sleeping virus. The virus persists in infected people’s cells for a lifetime, leaking EBNA1 into their bloodstreams all the way.

The new study … pointed to some genetic factors that may play a major role in determining which EBV-infected people develop multiple sclerosis.

That made EBNA1 a prime suspect. And it turned out that a narrow stretch of EBNA1 was very similar to a piece of a protein called GlialCAM that sits on the outermost membrane of oligodendrocytes, the myelin-producing cells.

Similar, but not identical. “There’s still enough of a difference between the two that our immune systems generally don’t get confused into mistaking one for the other,” Lanz said. Otherwise, an Epstein-Barr infection would always trigger MS.

But it’s known that from time to time, our cells’ enzymes snap tiny chemical caps onto specific spots on proteins that have already been made. The scientists showed that this can happen to GlialCAM, sometimes making it look all the more like EBNA1.

Meanwhile, when B cells (the antibody-producing immune cells) are continually stimulated by an ever-present immunogenic substance (like EBNA1), they keep on dividing. As they do, they mutate. The resulting mutant antibodies gradually diverge, some becoming more strongly targeted to the protein stretch they were originally generated to attack and others aimed at similar but not identical targets.

The researchers looked closely at B cells from MS patients to see how their antibodies differed from those of healthy people. They found that many patients’ B cells produced at least one antibody that grabbed firmly onto not only the telltale region of EBNA1 but also its look-alike stretch on some versions of post-production-modified GlialCAM.

That’s called molecular mimicry: similarity between a pathogenic and a human protein that confuses the immune system, which conflates the two. “This may explain how we could develop a strong immune response to EBNA1, and eventually to GlialCAM, over the decades,” Lanz said. It takes two to tango.

It may take a long time before Epstein Barr-infected people’s antibodies reach the stage where they’re pumping out antibodies directly targeting GlialCAM.

But, Lanz said, “Time is what EBV’s got.”

The 2022 study’s results were fleshed out and extended in a 2024 study in Proceedings of the National Academy of Sciences, conducted in collaboration with Karolinska Institute researchers. The new study, in addition to confirming all of the above, pointed to some genetic factors that may play a major role in determining which EBV-infected people develop multiple sclerosis.

There’s more where those came from

Numerous other examples of an “infection connection” link a pathogen to a chronic condition.

Cervical cancer is attributed to infection by the human papilloma virus. Ulcers, we now know, are mainly caused by a stomach-inhabiting bacterium, Helicobacter pylori.

Lanz co-authored a 2023 study led by Robinson that linked periodontal infection by bacteria to rheumatoid arthritis. Other Stanford Medicine researchers have identified infection-triggered autoimmune disorders. And more links will be found. Each such discovery is a concrete step toward finding a way to relieve humanity of the burden of chronic disease that weighs ever more heavily upon us.