In September 2009, the H1N1 swine flu had arrived in Portugal, Spain, and the UK, so France braced itself for cases.
Indeed, the number of people in France with respiratory symptoms soon increased. But they did not seem to have H1N1. France registered only sporadic positive tests for the new swine flu for most of that September and the first half of October. When H1N1 finally took hold in France, it was much later in the fall than expected. And that got scientists thinking: Why?
A flurry of papers since then have narrowed in on a beguiling hypothesis: The pandemic flu was deflected by the common cold.
For many people, COVID-19 has revealed, in terrifying detail, the bizarre nature of viruses. Beneath the surface of our daily lives is a constantly shifting ecology of pathogens that often behave in unexpected ways. In France in 2009, infections by rhinoviruses, which usually cause colds, were spiking when H1N1 was expected to arrive, and when they petered out, the pandemic flu took off. Since then, studies have found that instances in which people have two viruses at once are rarer than chance alone would predict. That suggests that having one protects you from the other, at least for a while — somehow.
During the COVID-19 pandemic, cases of many other respiratory infections have plummeted. This is likely a result of social distancing protocols, but it’s also possible that viral interference, the phenomenon of viruses affecting each other, may be involved. This insight could offer a head start on fighting future pandemics. With a deeper understanding of our viral ecology, what if, someday, we could use viruses against each other?
In recent years scientists have developed a much more sophisticated picture of what bacteria do to us and for us. They’ve been exploring how our health is shaped by the mix of beneficial and dangerous bacteria in our microbiomes. Now viruses may merit a reexamination as well.
The idea that viruses might interfere with each other is old — as old as vaccination. Edward Jenner, the English doctor who helped develop the practice of inoculating against smallpox in the 18th century, noticed it. Inoculation involved infecting a person with the milder cowpox virus. But if the patient had herpes, then it did not work as well. It was as if having two active infections at once altered how the immune system responded.
Over the next two centuries, scientists reported more and more situations in which it was clear that infections didn’t operate in a vacuum. One 1950 review article even called it a “well-known fact” that having one virus could inhibit the growth of another.
The topic is not frequently discussed these days, though. Viral interference that protects people can be difficult to study and is generally overlooked, says Stacey Schultz-Cherry, an infectious disease researcher at St. Jude’s Hospital in Memphis, Tenn. That’s because, she explains, situations in which simultaneous infections cause a worse prognosis are so much better known. The flu, for instance, is notorious for opening the door to bacterial pneumonia. Small studies from the beginning of the pandemic suggest having both the flu and COVID-19 is worse than having either alone.
But the worst-case scenarios might mask something profound about what often happens as our immune systems encounter viruses all day, every day, says Michael Mina, an epidemiologist at Harvard Medical School and Brigham and Women’s Hospital. “Viral infections may actually protect people from other viral infections — or bacterial infections — by stimulating immune responses, by keeping our innate immune system on its toes all the time, with these constant little pushes and nudges,” he says. “They are like training for us,” he suggests.
Adaptive immune defenses target specific pathogens, and these are what protect us after we’ve been vaccinated. But innate immunity is more all-purpose. After studying the H1N1 flu, Ellen Foxman, an immunologist at the Yale School of Medicine, and colleagues released a paper in October suggesting that once the innate immune system is activated by one pathogen, the body can repel another invader.
To model what might have been happening during the swine flu pandemic, the researchers grew human airway tissue in the lab and infected it with rhinovirus. Then, three days later, they gave it the H1N1 flu. They were intrigued to see that the flu virus just fizzled out, and they determined that the rhinovirus had switched on a number of genes that produce innate immune proteins. Suspecting that molecular messengers called interferons had flipped those switches, they treated the tissues with a drug that blocked interferons and ran the experiment again. “Lo and behold, the influenza grows just fine,” says Foxman. Interferons produced to fight the rhinovirus had been beating back the flu.
A number of viruses trigger the interferon response, and it’s possible that any of them could make the body put up stiff resistance to a new infection for some period of time. For instance, the team didn’t test whether having the flu first would stop a rhinovirus in its tracks, but it’s plausible, says Foxman. That might explain why flus and colds have alternating peaks every year. There are a lot of reasons why one virus might take center stage over others, including human behavior, school schedules, and climate. “But you really wonder if viral interference is one missing piece of that equation,” Foxman says.
In the current pandemic, the same questions are at play. While social distancing and masks are reducing the incidence of seasonal flu, perhaps the prevalence of COVID-19 is cutting it down further. Or, says Schultz-Cherry, maybe the flu would have slowed down COVID-19. They’re questions that can only be answered with further research, but they are worth asking.
Because the new research demonstrates how one infection can stop another, it hints at the possibility of unusual new therapies somewhere down the road. One can imagine viruses engineered to provoke just enough of a response to protect us against more dangerous things for, say, the next week — a benign infection to block an immediate threat. On a more practical level, says Schultz-Cherry, a protective interferon response might someday be generated in just the right places in the body by something like a nasal mist. For people at high risk, interference might provide a shield.
On the larger scale, these immune responses are the result of eons of coevolution between humans and viruses. Is it possible that after our long dance with these self-replicating snippets of genetic code, there are viruses that do us more good than harm? Mina suspects that medical research’s focus on the negative outcomes of viral infections may have blinded us to that reality.
“We miss these beautiful interactions that probably, evolutionarily, are completely working for and with us as humans, and not against us,” he continued. “The microbiome is a great example. . . . We saw bacteria everywhere and thought, maybe they’re good. Turns out they’re essential.”
Veronique Greenwood is a writer whose work has appeared in The New York Times, The Atlantic, and National Geographic, among other publications.