Immune Cells Are More Paranoid Than We Thought

The best immune systems thrive on a healthy dose of paranoia. The instant that defensive cells spot something unfamiliar in their midst—be it a living microbe or a harmless mote of schmutz—they will whip themselves into a frenzy, detonating microscopic bombs, sparking bouts of inflammation, even engaging in some casual cannibalism until they are certain that the threat has passed. This system is built on alarmism, but it very often pays off: Most of our encounters with pathogens end before we ever notice them.

The agents of immunity are so risk-averse that even the dread of facing off with a pathogen can sometimes prompt them to gird their little loins. Ashley Love, a biologist at the University of Connecticut, has seen this happen in birds. A few years ago, she stationed healthy canaries within eyeshot of sick ones, infected with a bacterium that left the birds sluggish and visibly unwell. The healthy canaries weren’t close enough to catch the infection themselves. But the mere sight of their symptomatic peers revved up their immune systems all the same, Love and her colleagues report today in Biology Letters.

Love, who did the research as a graduate student at Oklahoma State University, had an inkling that the experiment would work before she did it. In 2010, the psychologist Mark Schaller, at the University of British Columbia, and his colleagues described a similar reaction in humans looking through photos of people who were sneezing or covered in rashes. The study subjects’ immune cells then reacted aggressively when exposed to bits of bacteria, a hint that the pictures had somehow whipped the body into fighting form, Schaller told me.

That 2010 study, Love told me, “sort of blew my mind,” because it didn’t follow the typical trajectory of the immune system reacting to an ongoing assault. Instead, the cells were internalizing visual cues and buttressing themselves preemptively—raising shields against an attack that hadn’t yet happened, and perhaps never would. It was what you might call bystander immunity, and it was totally bizarre.

Love decided to try her own version in domestic canaries, among the many bird species susceptible to a pathogen called Mycoplasma gallisepticum. She infected 10 canaries with Mycoplasma, then placed them in sight of microbe-free birds. In parallel, she had two other cadres of healthy canaries scope each other out, as a symptomless point of comparison.

Throughout the 24-day experiment, the uninfected canaries acted as most songbirds do, feeding, chirping, and bopping cheerily around their cages. But about a week in, the birds dosed with Mycoplasma became mopey and lethargic, and developed a nasty form of pink eye. “I could approach the cage and just pick them up,” Love told me. (Some Mycoplasma species can cause disease in humans; this one doesn’t.)

The birds watching their beleaguered peers never got infected themselves. But when Love and her colleagues examined the canaries’ blood, they found that some of the birds’ immune responses had swelled in near lockstep with the sick birds’ symptoms. Cells called heterophils—inflammation-promoting foot soldiers that fight on the front lines of many avian infections—had flooded the bloodstream, similar to how they would in the presence of Mycoplasma, Love said. The birds’ blood was also rife with so-called complement molecules, which can shred bacterial cells, or flag them for other types of destruction.

The uptick was temporary. As the symptoms of the sickened birds abated, their observers’ immune cells quieted down as well. Love told me she suspects that these little flare-ups might have primed the watchful birds for a possible tussle with the pathogen—perhaps cloaking them in a light layer of armor, akin to a very crude and very ephemeral vaccine.

To confirm that idea, Love would have needed to expose the onlooker birds to Mycoplasma while their immune systems were still raring to go, an experiment she is working on now. Without those data, “it’s hard to know what this means,” Jesyka Meléndez Rosa, an immunologist at Humboldt State University who wasn’t involved in the study, told me.

The immunological surge did seem driven by the disease cues that the other birds emitted, because samples taken from the canaries who’d peeped on only healthy birds stayed comparatively inert. But what the researchers found could have just been a blip—noticeable, yet not strong enough to alter the trajectory of a subsequent infection. A bystander immune response could even be a net negative for the witness, wasting precious bodily resources or unnecessarily damaging healthy tissues. Heterophils and complement molecules also comprise just a small subset of the immune system’s arsenal, much more of which would be marshaled into quelling a Mycoplasma invasion. Letícia Soares, a disease ecologist at Western University who wasn’t involved in the study, told me she wished she’d been able to see how well the observer birds’ immune responses simulate what happens in infected birds who eventually recover.

Still, the potential payoff is “huge,” Meléndez Rosa said. A well-timed burst of immune activity, especially one kick-started in advance, could theoretically help the birds thwart illness and death, or maybe even stave off infection entirely. Birds are also “highly visual” animals, Soares told me, capable of tuning in to even slight changes in appearance. That intel could then spark a body-wide stress response, like a security camera tripping alarms throughout a well-protected building. “The idea of that is fascinating,” Soares said.

The connective tissue that links visual cues to immune activation is still scientifically foggy. At first, “it all seems kind of magical,” Schaller, the University of British Columbia psychologist, told me. But it’s also sensible (literally) for animals to glean information from their environment and react accordingly. “We’re stimulus-response devices,” he said. “We perceive something in some way, and our body responds.” Several experts told me that they wouldn’t be surprised if nonvisual signals—including the sounds, sensations, or even smells of a stranger’s sickness—could clue animals into the risks of infection as well. Love told me she hopes to figure out whether animals can tune their immune responses to the severity of the disease symptoms they see.

The paper speaks to the strange appeal of visible disease, says Cécile Sarabian, an expert in sickness behaviors at the Kyoto University Primate Research Institute who wasn’t involved in the study. The signs and symptoms of infection are often a pain for the individual who experiences them. But they also “alert others, and prepare other potential hosts,” she told me.

Spotting symptoms alone isn’t good enough. In the past year and a half, SARS-CoV-2 has benefited from its ability to spread silently from person to person. Humans have also taken a multitude of other measures—masking, distancing, and the like—to keep the coronavirus at bay, acts of avoidance that Schaller says count as a kind of behavioral immunity. Still, Schaller and others think it’s interesting to consider what sorts of infections count as truly “asymptomatic.” Even if an infected person isn’t feeling outright ill, they might be beaming out slight signals that betray their status, and influencing those around them. “We’re pretty sensitive to some pretty subtle stuff,” Schaller said. “It could be that we are able to pick up on other people’s sicknesses, even if those people are not yet aware.”

If an infection is to persist in a population long term, it must become communal; perhaps the experience of it is as well, in ways we don’t yet appreciate. Soares, who’s had long COVID for more than a year, told me that we urgently need to understand “how this societal crisis will affect our health in general.” This pandemic, and many that have come before it, is a reminder of what researchers are now starting to systematically define: Even those who aren’t directly touched by a pathogen can still feel its effects.