The bat-virus détente

For several weeks in March, Arinjay Banerjee would eat breakfast at 6am and then drive the empty roads of Toronto to a restricted-access lab. Then he’d ready himself for work, donning three layers of gloves, a helmeted mask kitted with an air-purifying respirator, and a surgical-style gown.

The interlocked doors and special filtered ventilation system of the lab, fitted with alarms should air circulation malfunction, are designed to stop outward air flow. After eight hours at the bench, Banerjee would put aside his scrubs and boot covers for sterilization, change out of his work sneakers and return to a basement apartment in the home of a colleague.

The stringent conditions in that Toronto lab—only one level below the most secure in the biosafety hierarchy—were crucial. Banerjee, a virologist, was on a team working to isolate the SARS-CoV-2 virus from one of the first patients in Canada. As the pandemic unfolded, he almost felt safer suited up in the containment lab than he did when out in the world.

The team was pushing to isolate the virus so they could get a jump on vaccine development. Banerjee was the bat guy. He had expertise in biosafety lab work and experience in isolating dangerous pathogens. He had studied how bats interact with viruses like the one that causes MERS, 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 the MERS virus, which has caused repeated outbreaks in people, bats also harbor very close relatives of the ones that caused the 2003 SARS outbreak and today’s COVID-19 pandemic. They are natural hosts for Hendra, Nipah and Marburg viruses—all of which can be deadly in people—and they are the suspected reservoir of the Ebola virus that has killed thousands in multiple outbreaks in Africa.

Bats can also host a diverse range of influenza viruses as well as relatives of the human-infecting hepatitis C virus. And research suggests that some viruses that today infect only people, like measles and mumps, had their evolutionary origins in bats.

Yet despite the long list of bat-dwelling viruses, the animals don’t seem to be bothered by their many invisible inhabitants. And 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 people. “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 manage to 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.

Before COVID-19 came along, 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—by stepping up activity of one immune protein, say, or dialing down activity of another—we might better understand how viral infections proceed in people. That, in turn, might point to treatments that could make infections in people 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.”

Suppress, then tolerate

The impressive ability of bats to ward off disease has long been remarked upon. A 1932 scholarly note on fruit bats in Australia states, “No reliable evidence of the occurrence of epidemics among the fruit-bat population was discovered.” And a 1957 paper on the southeastern myotis bat notes that “disease is apparently unimportant…. During the course of this study, which involved observations on over a million bats in every known cave colony in Florida, I have never found a dead bat, and have seen only one which appeared diseased.”

Certainly, bats in the United States are in trouble today: The Eurasian fungus behind white nose syndrome has been killing large numbers of many bat species for more than a decade. But with few exceptions—including rabies and the more obscure Tacaribe virus—when bats get infected with viruses they don’t appear to get sick.

“There seems to be no pathology associated with these infections—no clinical signs associated. 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 who coauthored a new review on bats and viruses.

When a host, whether bat or human, is infected with a disease-causing pathogen, the ensuing interaction is often described as a battle: The host’s immune system pulls out the big guns to fight and eradicate the invader. In immunology parlance, this is known as resistance; its end game is destroying the pathogen.

But there’s a growing appreciation of the importance of disease tolerance, a “keep calm and carry on” approach in which the immune system limits collateral damage to the host but doesn’t worry about getting rid of every trace of a pathogen. And several recent studies suggest that this tolerance model captures how bats interact with many of the viruses they carry.

Many details are missing: There are some 1,300 bat species—they are the second largest order of mammals, outnumbered only by rodents—and studies typically focus on one or a handful. But a rough picture is emerging. Research suggests that the bat immune system deals with marauding viral invaders in two key ways: 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.

“Bats have a lot of this good immune response—suppressing virus replication—that protects them,” Banerjee says. “And they have very little of the not-so-good immune response, which is inflammation.”

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: Large flying foxes (Pteropus vampyrus) and little brown bats (Myotis lucifugus) have dozens of genes for making even just one kind, called type 1 interferons; the Egyptian fruit bat ( Rousettus aegyptiacus), a natural host of Marburg virus, has 46 (humans have about 20).

Black flying foxes (Pteropus alecto) seem to use another strategy: In this species—as well as the lesser short-nosed fruit bat ( Cynopterus brachyotis)—some genes for making interferons are always turned on, even when there’s no viral invader to contend with. In the black flying foxes, these “always on” interferons, among other things, kick-start production of an enzyme that chops up viral genetic material.

Black flying foxes and big brown bats (Eptesicus fuscus) have yet another trick up their wings. They have an extra-strong version of a protein whose job is to flip the “on” switch for some interferon genes. Experiments by Banerjee and colleagues using genetically altered human and bat cells found that in either kind of cell, the bat protein was better than the human version at keeping viral numbers down after exposure to a cousin of the rabies virus.

Bats, in other words, seem to have multiple layers of interferon protection: one that stands at the ready to quickly curtail viral replication, and another, more standard-issue one that ramps up activity after a viral invader has appeared. But it’s not just a blunt one-two punch. The sheer number of interferon genes some bats have hints at a flexible, more nuanced response.

Having many, many copies of a gene presents opportunities, says Thomas Kepler, a computational immunologist at Boston University’s medical school, who’s done much of the Egyptian fruit bat research. Some of the genes can ramp up or down their activity even as other ones keep normal functions going. Rather than all of the interferons sounding the standard “prepare for war” alarm, some may tell cells to hold their fire and sit tight.

The message, Kepler says, may be, “We’ve got a virus, let’s use soft power for as long as we can.”

https://arstechnica.com/?p=1689326