Banerjee was the bat guy. He had expertise in isolating dangerous pathogens. And he’d studied how bats interact with viruses like the one that causes the Middle East respiratory syndrome, one of hundreds of coronaviruses that the mammals can harbor.
Bats have become newly infamous as reservoirs of deadly viruses. In addition to hosting an ancestral version of MERS, which has caused repeated outbreaks in people, bats also harbor very close relatives of the virus that caused the 2003 severe acute respiratory syndrome outbreak and today’s novel coronavirus pandemic. They are the suspected reservoir of the Ebola virus and natural hosts for Hendra, Nipah and Marburg viruses — all of which can be deadly in people.
But despite the long list of bat-dwelling viruses, the animals don’t seem to be bothered by their many invisible inhabitants. Scientists want to know why.
Today, a growing number of them suspect that the key lies in special features of the bat immune system — ones that spark responses to viral invasion that are very different from what goes on in humans.
“It’s very intriguing,” Banerjee says. “I wake up thinking about it every day. Why do bats have this immune response that’s so different from ours and so different from other mammals?”
Of course, many viruses exist in wildlife, often causing little harm to their natural hosts and only making trouble for us when they jump to human beings or other creatures with which they don’t share a long evolutionary history. Ducks and other water birds muck about while carrying myriad strains of influenza A; pigs aren’t fazed by hosting hepatitis E.
But bats appear to be special, if only in the number of high-profile viruses that they carry and appear to tolerate. With few exceptions — including rabies and the more obscure Tacaribe virus — when bats get infected with viruses they don’t appear to get sick.
“They can remain in good health and display no discernible signs of disease,” says Raina Plowright, an infectious-disease ecologist and wildlife veterinarian at Montana State University in Bozeman.
Before covid-19, scientists already were piecing together some of the peculiarities of the bat-virus relationship. That research has taken on new urgency, and it raises an intriguing possibility. If we better understand how bats tolerate their viral passengers, it might point to treatments that could make human infections less severe.
“Rather than trying to reinvent the wheel, we could learn from what evolution has developed in a bat, where the outcome is not disease but it’s something that enables survival upon infection with a particular virus,” says cellular immunologist Judith Mandl of McGill University in Montreal. “If we figure that out, then maybe we can apply the same principles and modulate the immune response in humans.”
When a host, whether bat or human, is infected with a pathogen, the ensuing interaction is often described as a battle. But there’s a growing appreciation of the importance of disease tolerance, a “keep calm and carry on” approach by the immune system, which limits damage to the host but doesn’t worry about getting rid of every trace of a pathogen.
Although many details are missing — there are some 1,300 bat species, and studies typically focus on one or a handful — recent studies suggest that such tolerance captures how bats interact with many of the viruses they carry.
First, the bats mount a speedy but nuanced offensive that stops the virus from multiplying with abandon. Second, and perhaps more important, they dial down the activity of immune foot soldiers that might otherwise cause a massive inflammatory response that would do more damage than the virus itself.
Key players in this two-part bat immune response are interferons, small signaling molecules that got their name because of their talent for interfering with virus replication. They’re a first line of defense for mammals in general: When cells are infected by viruses, they release various interferons as an alarm signal, as do some immune system cells.
But bats seem to go one better. To start with, some species have an outsize number of genes for making interferons. For example, the Egyptian fruit bat (Rousettus aegyptiacus), a natural host of Marburg virus, has 46 such genes (humans have about 20).
Second, species like black flying foxes (Pteropus alecto) keep some genes for making interferons active all the time, even when there’s no viral invader to contend with. One of the things these “always on” interferons do is kick-start production of an enzyme that chops up viral genetic material.
Bats also seem able to tame inflammation, which is essential for fighting infections, but also can be catastrophic.
Out-of-control inflammation is a common theme in severe illnesses from viruses that have jumped from other species: In people infected with deadly filoviruses like Ebola, for example, a bombardment of inflammation-causing molecules spurs the failure of multiple organs and a septic shocklike syndrome.
And some novel strains of influenza, including the one that caused the deadly 1918 pandemic, are especially adept at triggering a barrage of inflammatory molecules. This prolonged blitz — which can manifest as what’s called a cytokine storm — was also found in people who fared poorly with SARS, and is what kills many of the sickest patients with covid-19.
“If you get infected with something, the immune response is always walking this tightrope,” Mandl says. “It’s a balance between making sure the response is vigorous enough — but not so vigorous that, for example, you end up with the lungs filling with fluid and a lot of inflammatory cells.”
Bats walk this tightrope with finesse. They seem to have several ways to avoid the dangerous inflammation overreaction.
For example, a study of immune cells in the greater mouse-eared bat (Myotis myotis) found dialed-up production of interleukin-10, a protein known to suppress the body’s inflammatory responses.
Bats also tamp down activity of large protein clusters called inflammasomes, which coordinate the release of all sorts of inflammation-promoting molecules.
And several bat species no longer make certain proteins that sense damaged genetic material and kick off an inflammatory response. At least 10 species of bats have lost an entire family of such proteins, for example.
Add it all up, and bats “really seem to throttle inflammation,” says evolutionary biologist Emma Teeling of University College Dublin, co-founder of a major effort to explore bat genomes.
As researchers parse how bats coexist with so many viruses, they are also asking why the creatures are this way. The answer may seem surprising: The tolerance could be connected to the fact that bats fly.
Bats are the only mammals capable of sustained, powered flight (they don’t just glide), a feat that required changes in metabolism. Flight is a major workout — estimates suggest a bat’s metabolic rate can increase to up to 34 times over its resting level when it takes to the air. This metabolic uptick during flight generates damaging chemicals called reactive oxygen species that trigger inflammation, which contributes to all sorts of maladies in mammals.
So, scientist hypothesize, by evolving to tamp down flight-associated inflammation, bats may also escape the dangerous inflammation triggered by viral infections.
The study of bats also has more immediate goals. “It’s really important to study bats in nature, to understand where the viruses are so that we can try to understand why they are coming from those populations and killing people,” says epidemiologist David Hayman of Massey University in New Zealand, who wrote an overview on bats and viruses in the Annual Review of Virology.
Recent research suggests that stressful conditions such as food shortages and habitat loss may be key predictors of bats shedding lots of virus. Plowright has spent years capturing bats in giant nets and sampling their blood, urine and feces, and has found that viral infections in bats are not consistent across time and space.
And stress aside, increased contact itself is problematic. “Just the simple fact of more people, more habitat destruction, means more potential contacts, which may just simply increase chances of an infection,” Hayman says.
Trying to eliminate such encounters by eliminating bats is not the answer. “That would be a disaster,” Plowright says. “They provide huge ecosystem services.” Bats are crucial pollinators of hundreds of plants, they aid in seed dispersal, and many are voracious eaters of insects.
Scientists know they’ve only just begun to parse the relationship between bats and the viruses they harbor, or to understand the occasional, catastrophic viral crossovers into our species. With the covid-19 pandemic roiling on, they have expressed dismay and astonishment at the recent termination of funding for some bat and coronavirus research by the National Institutes of Health.
But they are pushing ahead with their work. For his part, Banerjee, now at McMaster University in Hamilton, Ontario, finds himself yet again suited up hazmat-style. He spends his hours nurturing petri dishes of bat kidney cells and growing up flask gardens of virus, then combining the two for infection experiments.
“I thought grad school was busy,” he says. “But this is insanely busy.”
This report was produced by Knowable Magazine and can be read in full at knowablemagazine.org.