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What about a bat's immune system protects them from Ebola?

What about a bat's immune system protects them from Ebola?


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Current evidence indicates that fruit bats are a reservoir host for Ebola. Has any research established what is different about their cell biology or immune system that reduces virulence for them? Failing research on this particular system, do you have an example in another system of how virulence is reduced in the reservoir host?

I'm teaching a cell biology class, so actual examples of modified proteins or enzymes or inflammatory molecules in the reservoir is preferred.


The main reason for this is that fruit bats are most likely (I don't think there has been a direct proof for Ebola so far) the reservoir host for this disease. The reservoir host is adapted to the disease and can harbour it for an indefinite time (with recurring infections) without showing signs of an infection or being affected by it. Although it is not getting sick, the reservoir host can pass the disease to other animals.

There is very little known about the immune system of bats, but they seem to be different, so they are not affected by diseases which cause havoc in humans. The following papers go into some details and they are interesting to read:

These papers give an interesting view of the bats immune system. The first article is a short explanation of the most important findings of the second. It looks into differences between species and analyse how the bats immune system may have evolved. Really interesting.

  • Of bats, flight and immunity to viruses
  • Comparative analysis of bat genomes provides insight into the
    evolution of flight and immunity.
  • Antiviral Immune Responses of Bats: A Review

Bat 'super immunity' could help protect people

Black-headed flying fox amongst a grey-headed colony. Credit: Michelle Baker CSIRO

For the first time researchers have uncovered a unique ability in bats which allows them to carry but remain unaffected by lethal diseases.

Unlike humans, bats keep their immune systems switched on 24/7 and scientists believe this could hold the key to protecting people from deadly diseases like Ebola.

Bats are a natural host for more than 100 viruses, some of which are lethal to people, including Middle Eastern Respiratory Syndrome (MERS), Ebola and Hendra virus, however, interestingly bats do not get sick or show signs of disease from these viruses.

Published today in the journal Proceedings of the National Academy of Sciences (PNAS), this new research examines the genes and immune system of the Australian black flying fox, with surprising results.

"Whenever our body encounters a foreign organism, like bacteria or a virus, a complicated set of immune responses are set in motion, one of which is the defense mechanism known as innate immunity," leading bat immunologist at CSIRO's Australian Animal Health Laboratory Dr Michelle Baker said.

"We focused on the innate immunity of bats, in particular the role of interferons - which are integral for innate immune responses in mammals - to understand what's special about how bats respond to invading viruses.

"Interestingly we have shown that bats only have three interferons which is only a fraction - about a quarter - of the number of interferons we find in people.

"This is surprising given bats have this unique ability to control viral infections that are lethal in people and yet they can do this with a lower number of interferons."

The team also compared two type 1 interferons - alpha and beta.

The research showed that bats express a heightened innate immune response even when they were not infected with any detectable virus.

"Unlike people and mice, who activate their immune systems only in response to infection, the bats interferon-alpha is constantly 'switched on' acting as a 24/7 front line defence against diseases," Dr Baker said.

"In other mammalian species, having the immune response constantly switched on is dangerous - for example it's toxic to tissue and cells- whereas the bat immune system operates in harmony."

While we are familiar of the important role bats play in the eco-system as pollinators and insect controllers, they are also increasingly demonstrating their worth in potentially helping to protect people from infectious diseases.

"If we can redirect other species' immune responses to behave in a similar manner to that of bats, then the high death rate associated with diseases, such as Ebola, could be a thing of the past," Dr Baker said.

This work builds on previous research undertaken by CSIRO and its partners to better understand bat immunity to help protect Australia and its people from exotic and emerging infectious diseases.

Led by CSIRO, this international research effort included expertise from CSIRO, Duke-NUS Medical School and the Burnet Institute.


Bats frequently come into contact with infectious diseases, but rarely suffer from them

The mastiff bat originates from from Central and South America. The animals possess an effective immune system which protects them from infections. Credit: MPI f. Ornithology

The bat's immune system works in a fundamentally different way to that of other mammals. This was the conclusion reached by scientists from the Max Planck Institute for Ornithology in a study of mastiff bats. The research could also be significant in the fight against viral diseases that can be transmitted from animals like bats to humans.

While bats qualify as carriers and reservoir hosts of a whole range of infectious diseases, very little research has been conducted on their immune system to date. Researchers from the Max Planck Institute for Ornithology in Radolfzell, the University of Konstanz and the Smithsonian Tropical Research Institute in Panama are now trying to bridge this gap. Their findings show that the immune system of bats may work in a way that is fundamentally different to that of other mammals. The immune defence of the animals could even provide clues as to how certain infectious diseases can be averted.

Many of the 1,300 known bat species have antibodies in their blood to protect against various diseases but rarely have the pathogens themselves. The animals seem to be able to fight off the pathogens without becoming ill themselves. But what makes their immune system so special?

The scientists studied the immune responses of Pallas's mastiff bats (Molossus molossus) in Panama. The animals follow a specific daily routine: during the day they reduce their energy consumption in their roosts in order to save energy. During this period, the bats rest motionless and their body temperature drops. It's only at sunset, when the mastiff bats set out for the hunt, that they come to life. Now, their body temperature rises to more than 40 degrees Celsius as their muscles need to work hard during their flight.

However, the high temperature could also have a side effect: it could activate the immune response against pathogens as a type of daily fever. Conversely, the daily slowdown in their metabolic rate could also inhibit the proliferation of existing pathogens in the body.

To test this hypothesis, the researchers administered a lipopolysaccharide (LPS) – a compound, harmless in itself, made up of lipid and sugar components – to the bats. As LPS is also found on the outer membrane of many pathogens, the bat's immune system assumes a bacterial attack and switches to defence mode.

As the scientists demonstrated, however, the daily temperature fluctuations remained unchanged even after the administration of LPS. The material therefore does not trigger a fever in the bats, as it does in other mammals. Furthermore, the number of white blood cells in the blood – an indicator of the strength of the immune defence – did not increase. However, the bats did lose a significant amount of mass within 24 hours – a sign for the researchers that the animals mobilise energy reserves for the immune defence.

"This mass loss also occurs in other bat species," explains Teague O'Mara, lead author of the study. "This is an indication that their immune system is switched on." Up until now, however, nobody could say exactly which cellular processes were taking place. "The immune system in bats does not behave in the same way as in other mammals," says Dina Dechmann from the Max Planck Institute for Ornithology. "We need to understand what makes it so special. It could help us to learn a lot about diseases that are dangerous to humans."

Thus, it is conceivable that bats could be unjustly blamed for Ebola. In a survey, scientists from the Robert Koch Institute and the Max Planck Institute are systematically analysing the current level of knowledge about the origin of the Ebola virus. According to the researchers, fruit bats cannot be the main or only reservoir. The Ebola virus itself has not yet been established in bats.

The chain of evidence so far is based on antibodies against Ebola, which have been discovered in the blood of fruit bats. The animals therefore may well come into frequent contact with the virus but are in a position to fight it off. A similar situation could arise with other infectious diseases which can be transmitted from animals to humans, such as rabies. In this case as well, an effective immune system could protect the bats from becoming ill. "If we could understand how the animals cope with the diseases, we could use this knowledge to develop new vaccines and medications," says O'Mara.


Why Bats Are Such Good Hosts for Ebola and Other Deadly Diseases

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Straw-colored fruit bat (Eidolon helvum). Steve Gettle / Getty

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Some of the planet’s scariest, most lethal viruses find a natural refuge inside bats, including Ebola, rabies, Marburg and the SARS coronavirus. Many high-profile epidemics have been traced to bats, and scientists are discovering new bat-borne viruses all the time.

The animals seem especially adept at harboring and spreading disease. Scientists trying to understand why have found some promising leads in bat genomes, but others argue bats’ notoriety as viral carriers isn’t justified.

“Are bats special? I still say it’s too early to answer,” says Linfa Wang, who leads research groups at CSIRO’s Australian Animal Health Laboratory and the Duke-NUS Graduate Medical School in Singapore. He's spent the last two decades studying bat-borne viruses and hunting for characteristics that might make the animals such great viral hosts.

“The question is so important we just can’t ignore it anymore,” he says.

Bats and other species that chronically harbor viruses, such as rats or mice, are known as disease reservoirs. Most of the time, these reservoirs stay intact, with infected animals rarely showing symptoms of disease. But sometimes they leak, letting a virus infect new, much more vulnerable species. This is almost certainly what happened with the ongoing Ebola outbreak in West Africa, which began with a trickle in December and has since infected at least 8,900 people and killed more than 4,400. Scientists suspect bats are to blame for this epidemic, which has overwhelmed Guinea, Sierra Leone, and Liberia.

Anecdotally, bats certainly appear to carry a disproportionately high number of scary viruses. But whether this is actually true remains an open question.

Scientists essentially fall into two camps on this issue. One school of thought says bat-related epidemics are simply a numbers game the idea is there are so many species and so many individuals that the emergence of bat-borne illnesses isn’t surprising. The other suggests bats are indeed special, that there’s something about their physiology or their lifestyle that makes them exceptionally good viral repositories.

What that something is has yet to be determined, but Wang and his colleagues have spent a good chunk of time trying to sort it out. They began by looking at bat genomes, hoping to find a clue in the bats’ immune system, like a set of genes that only bats have.

Last week, authorities in Spain euthanized a dog whose owner had become infected with Ebola after treating a missionary who’d been in West Africa. Many argued the response was extreme and unwarranted, citing a lack of evidence dogs can transmit Ebola.

During the 2001-2002 Gabon outbreak, researchers found roughly 25 percent of the dogs from villages with human Ebola cases tested positive for Ebola antibodies. But dogs from villages without human cases also tested positive. And so did two dogs in France that presumably never encountered anything carrying the virus. None of the animals became symptomatic or died, so the question remains open as to whether dogs can be infectious.

Tracing the routes from reservoir to humans is tricky. Even now, scientists don’t know all the pathways Ebola can take from bats to humans. One known mode of transmission is eating an infected animal. Bats, primates, and other wildlife often are consumed in parts of West Africa. Now, people are being warned about the risk of consuming bushmeat.

Other pathways are less clear. Saliva, urine or feces from infected fruit bats could contaminate fruit that might then be eaten by a human, or intermediate host. This can be the case with Nipah and Hendra viruses. In Bangladesh, Nipah virus appears to pass directly from bats to humans via date palm sap. In Southeast Asia, Nipah first infects pigs, which then infect humans. In Australia, Hendra appears to use horses as an intermediate species. And Ebola has infected primates that people then eat.

Instead, the team uncovered a more subtle difference: Even though bat genomes contain many of the same ingredients as other mammals, bats use them differently. In particular, the bat genes coding for proteins that detect and repair damaged DNA are much more prevalent than expected. More simply, those genes are believed to be doing something that helps the bats survive and reproduce, so that those genes are passed on to subsequent generations.

These results, reported in the journal Science in December 2012, correspond with the previous observation that DNA damage repair genes are frequent targets for invading viruses, which could be what is applying the evolutionary pressure. The findings also mesh with the anecdotal observation that bats rarely (if ever) develop tumors—perhaps because the repair genes can outpace any malignant growth.

Since then, Wang and his colleagues have gone a step further. Newer, still-unpublished findings suggest that unlike in humans or mice, where defenses such as anti-tumor and anti-viral genes are activated only in response to a threat, in bats these genes seem to be perpetually turned on. That activity keeps levels of any harbored viruses simmering below the point at which they could cause harm. In other words, evolution has conspired to turn bats’ surveillance mechanisms up to 11.

As for why, Wang suggests a link with flight, which boosts a bat’s metabolic rate to a level many times higher than when it is resting. Such sustained energy production generates stress that can damage cells and DNA if it isn’t quickly detected and repaired.

So perhaps initially, those damage-repair proteins got turned way up to combat the damage caused by bats doing what bats do, which is flying around every night. If true, the ability to carry lethal viruses might have come second, as a sort of coevolutionary accident, Wang says.

Another hypothesis, reported in *Emerging Infectious Diseases *in May, suggests bat flight might generate enough heat to mimic a fever. As part of the normal immune response in many animals, fevers help combat infection by raising body temperature to levels that will kill or disable invading pathogens. By raising their temperatures, the hypothesis suggests, flying might inadvertently be dialing back bats’ viral load each night.

Though no experiments have been done to test the idea, some scientists say it’s plausible that one reason bat-borne viruses are so lethal when they spill over into humans or other animals is because they’ve evolved to withstand the bat’s especially active immune system.

“We don’t have that sort of immune system,” says Angela Luis, a disease ecologist at the University of Montana, and an author of the fever-flight study. Once free from the bat’s hyper-vigilant, perpetually turned on defenses, those viruses might have no problem overwhelming more feeble immune systems.

Wang isn’t yet ready to conclude bats are especially good viral hosts, but believes the scientific field is creeping closer to accepting that possibility.

The other possibility is that what’s happening is simply a combination of numbers and opportunity, that bat-borne spillovers are nothing more than statistics at work.

With more than 1,200 known species, bats comprise more than 20 percent of the mammal species on Earth. And among mammals, they’re outnumbered only by rodents (contrary to popular belief, bats are not rodents). But in many areas, bats are more numerous than rodents, with millions of individuals sometimes living in a single colony.

The perception that bats are somehow special may be colored by high-profile outbreaks and a disproportionate amount of work focused on bats as viral vessels. “The self-fulfilling prophecy, which I would warn against, is that the more we dig, the more viruses we’re going to find,” said Kevin Olival, a disease ecologist at EcoHealth Alliance.

An Indian flying fox (Pteropus giganteus) eats fruit on a beach in Sri Lanka.

In a 2013 study, Olival and colleagues examined the virome of a giant bat called the Indian flying fox (Pteropus giganteus). In that one species, they detected 55 viruses, 50 of them previously unknown. That’s roughly the total number of bat viruses identified in a seminal 2006 study that reviewed all of the relevant research done at the time. In the intervening eight years, though, that number has doubled or tripled or more, depending upon the criteria used to define “known virus.”

But Olival argues that trend is not unique to bats. “If you look at the broad spectrum of what we know about mammal virus diversity, all have pretty diverse groups of viruses,” he said. “The groups that don’t are the ones we haven’t looked at enough.”

The question, then, is why do we keep hearing about bat-borne epidemics?

"I think the important thing is ecology, and thinking about where these animals live, and how humans are coming into contact with them,” Olival says. He suggests that what's really important is the way humans interact bats -- or rather, the ways in which humans are interacting with and encroaching upon bat habitat.


Could a special immune system help protect bats from Ebola?

The bat's immune system works in a fundamentally different way to that of other mammals. This was the conclusion reached by scientists from the Max Planck Institute for Ornithology in a study of mastiff bats. The research could also be significant in the fight against viral diseases that can be transmitted from animals like bats to humans.

The mastiff bat originates from from Central and South America. The animals possess an effective immune system which protects them from infections.

While bats qualify as carriers and reservoir hosts of a whole range of infectious diseases, very little research has been conducted on their immune system to date. Researchers from the Max Planck Institute for Ornithology in Radolfzell, the University of Konstanz and the Smithsonian Tropical Research Institute in Panama are now trying to bridge this gap. Their findings show that the immune system of bats may work in a way that is fundamentally different to that of other mammals. The immune defence of the animals could even provide clues as to how certain infectious diseases can be averted.

Many of the 1,300 known bat species have antibodies in their blood to protect against various diseases but rarely have the pathogens themselves. The animals seem to be able to fight off the pathogens without becoming ill themselves. But what makes their immune system so special?

The scientists studied the immune responses of Pallas&aposs mastiff bats (Molossus molossus) in Panama. The animals follow a specific daily routine: during the day they reduce their energy consumption in their roosts in order to save energy. During this period, the bats rest motionless and their body temperature drops. It&aposs only at sunset, when the mastiff bats set out for the hunt, that they come to life. Now, their body temperature rises to more than 40 degrees Celsius as their muscles need to work hard during their flight.

However, the high temperature could also have a side effect: it could activate the immune response against pathogens as a type of daily fever. Conversely, the daily slowdown in their metabolic rate could also inhibit the proliferation of existing pathogens in the body.

To test this hypothesis, the researchers administered a lipopolysaccharide (LPS) – a compound, harmless in itself, made up of lipid and sugar components – to the bats. As LPS is also found on the outer membrane of many pathogens, the bat&aposs immune system assumes a bacterial attack and switches to defence mode.

As the scientists demonstrated, however, the daily temperature fluctuations remained unchanged even after the administration of LPS. The material therefore does not trigger a fever in the bats, as it does in other mammals. Furthermore, the number of white blood cells in the blood – an indicator of the strength of the immune defence – did not increase. However, the bats did lose a significant amount of mass within 24 hours – a sign for the researchers that the animals mobilise energy reserves for the immune defence.

“This mass loss also occurs in other bat species,” explains Teague O’Mara, lead author of the study. “This is an indication that their immune system is switched on.” Up until now, however, nobody could say exactly which cellular processes were taking place. “The immune system in bats does not behave in the same way as in other mammals,” says Dina Dechmann from the Max Planck Institute for Ornithology. “We need to understand what makes it so special. It could help us to learn a lot about diseases that are dangerous to humans.”

Thus, it is conceivable that bats could be unjustly blamed for Ebola. In a survey, scientists from the Robert Koch Institute and the Max Planck Institute are systematically analysing the current level of knowledge about the origin of the Ebola virus. According to the researchers, fruit bats cannot be the main or only reservoir. The Ebola virus itself has not yet been established in bats.

The chain of evidence so far is based on antibodies against Ebola, which have been discovered in the blood of fruit bats. The animals therefore may well come into frequent contact with the virus but are in a position to fight it off. A similar situation could arise with other infectious diseases which can be transmitted from animals to humans, such as rabies. In this case as well, an effective immune system could protect the bats from becoming ill. “If we could understand how the animals cope with the diseases, we could use this knowledge to develop new vaccines and medications,” says O&aposMara.


Limiting the damage

If there’s a lesson to learn from bats about tolerating viral infections, it isn’t that we should learn to fly. But we may be able to learn how to limit inflammation-incurred damage.

“Tolerance can really be seen as a different way of dealing with the pathogen,” Mandl says. “It’s still very much an immune strategy. But the strategy is not to try to clear the pathogen, or maybe not even to greatly reduce replication, but just to limit the collateral damage.”

Hendra virus, which is carried by Australian bats known as flying foxes, can be transmitted to horses via contact with contaminated bat feces, urine or saliva horses can then infect people. Here, PhD student Tamika Lunn collects such samples under a flying-fox roost in subtropical Australia after a Hendra spillover event to horses.

There may be insights to gather from other animals that tolerate disease-causing pathogens, too. Mandl has found that sooty mangabey monkeys, which carry but aren’t sickened by a close relative of HIV called simian immunodeficiency virus, also have a dialed-back interferon response.

And Tony Schountz, a viral immunologist at Colorado State University, says the same sort of thing occurs in the mice, rats and shrews that happily host hantaviruses. “They have this anti-inflammatory immune response to what’s to them a rather innocuous virus,” he says. “In people, there’s this massive inflammatory response that occurs it’s thought that that’s the principal contributor to the disease and the death of humans.”

Understanding these “successful” immune responses, Schountz adds, could one day lead to strategies to mitigate disease severity in people. Say, for example, you knew what parts, or which molecules, of the immune system need to be tamped down to avoid inflammation when a virus infects. Then “you could develop a therapy or drug that can disrupt that pathway to prevent the inflammatory response from occurring,” he suggests.

The study of bats has more immediate — and urgent — goals, though. “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.

Given the outbreaks that have been linked to bats in recent years — several coronaviruses, Hendra, Nipah, Ebola, Marburg and many more — he and other infectious-disease researchers say it’s of paramount importance to understand the likelihood of future spillover events. The question warrants addressing from several angles.

Though it’s known that many bats harbor many viruses, studies examining the dynamics of infections over time, and of more than one virus at a time, are rare. In one such study, researchers looked for nine kinds of paramyxoviruses in Australian bats over several months by placing plastic sheets beneath roosts and sampling the urine. Shown are data from two sites in Queensland with mixed roosts of black flying foxes and grey-headed flying foxes. While the average number of viral detections per urine sample is low — either the viruses were not present or were at levels too low to be detected — there were brief, extreme periods when multiple viruses were found. For example, such a spike occurred in the Australian winter of 2011 (the Northern Hemisphere’s summer) during this period, RNA of up to six unique viruses were detected per sample (a mean of 1.8). This coincided with a large cluster of spillover events of the Hendra paramyxovirus to horses and with a period of food shortage that stressed the bats.

The type of virus involved clearly matters. Many of the high-consequence ones that have made the jump from bats to people in recent years use RNA as their genetic material. The machinery used by many of these viruses to copy their genomes is particularly sloppy, which means that errors — new mutations — can quickly accrue, raising the odds of hitting upon mutations that allow the virus to switch hosts. (Coronaviruses aren’t as sloppy as some, but still accumulate changes by frequently trading chunks of genome back and forth.)

Also important are the types of human-bat interactions: Which ones are the most risky? “If you think about coronaviruses, they are found in bats all over the world,” Hayman says. “So another way of looking at this is: Why don't all those infections cause outbreaks?”

Recent research suggests that stress is important — it may be a key predictor of bats shedding lots of virus. Plowright has spent years capturing bats in giant nets and sampling their blood, urine and feces, and finds that viral infections in bats are not consistent across time and space. In fact, much of the time, viruses can’t be detected at all.

“We’ll look again and again, over and over, and we won’t find anything,” she says. “And then we’ll come back the next month and sample again, and we might find a large proportion of the bats are actually infected with the virus.”

Those obvious infections may last a couple of months, then disappear. In the flying foxes of Australia, peak periods of infection — which coincide with Hendra virus spillover events — occur during the birthing season. Other types of stress, such as food shortages or habitat loss, also may drive periods of viral shedding. Hayman and colleagues have found that land use changes in West Africa — resulting in fragmentation of the forests in which bats live — coincide with outbreaks of Ebola.

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, experts stress. “That would be a disaster,” Plowright says. “They provide huge ecosystem services.” Bats are crucial pollinators of hundreds of plants including many agriculturally important ones. They aid in seed dispersal, and many are voracious eaters of insects — mosquitos and crop pests importantly among them. And eliminating bats can backfire, with deadly consequences: Killing Egyptian fruit bats in a mine in Uganda led to an influx of new bats and a Marburg virus outbreak, scientists think.

Studying bats — most of which are nocturnal and can fly great distances — is difficult enough. But there’s also a lack of basic experimental tools for work on bat-virus relationships, since lab equipment and protocols are typically designed with rodents and human tissues in mind. While recent years have seen progress, the toolkit wish list remains long. Establishing stable, reproducing bat cell lines has been achieved only for a handful of bat species and often for just a few cells types, such as kidney or lung. Researchers also lack many lab reagents tailored for bats, such as ones that can be used to study the animals’ antibodies. Growing viruses within genetically altered bat cells could help to track the course of infection in live bats. It could also aid in the development of vaccines and diagnostic tests.

Scientists know they’ve only just begun to parse the relationship between bats and the medley of viruses they harbor, as well as the whys and wherefores of those occasional, catastrophic viral crossovers into our own species. Other features of bats, such as the close-quarter colony living of many species and the extremely low body temperatures of hibernation, also may play key roles in bat-virus dynamics.

There is much work to do, much of it difficult. Even straightforward experiments can be tricky because lab protocols and reagents have been tailored for human tissues and mice, not chiropterans. With the Covid-19 pandemic roiling on, scientists have expressed dismay and astonishment at the recent termination of funding for bat and coronavirus research by the National Institutes of Health. But they are pushing ahead with their work.

Banerjee, for his part, finds himself yet again suited up hazmat-style and scrupulously swapping out shoes at day’s end. 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, a version of nature’s bat-virus détente writ small.

For the time being, he’s focused on SARS-CoV-2, but still as a bat guy, now as a postdoc at McMaster University in Ontario. “I thought grad school was busy,” he says. “But this is insanely busy.”

Rachel Ehrenberg is the associate editor of Knowable Magazine.


Lurking in the Shadows

Bob Grant
Dec 1, 2014

© INGO SCHULZ/IMAGEBROKER/CORBIS

I n a dusty, subterranean room beneath a crumbling sand building a few miles north of Naqi, Saudi Arabia, EcoHealth Alliance veterinary epidemiologist Jon Epstein finally found what he was looking for: bats. It was early October 2012 he&rsquod travelled to the country with a team of scientists at the request of the Saudi Ministry of Health. A researcher in Jedda had isolated RNA from a strange virus found in the mucus coughed up by a 60-year-old Saudi businessman who&rsquod recently suffered acute pneumonia and renal failure. The man, whose main place of business was located in Naqi, died 11 days after being admitted into the hospital in mid-June.

Epstein and Columbia University epidemiologist Ian Lipkin had been scouring the man&rsquos homes and businesses around the desert town of Bishah in search of the source of the deadly virus. They were intent on sampling bats because a.

So when Epstein and Lipkin were summoned to Saudi Arabia to hunt down the new coronavirus, which would become known as the Middle East respiratory syndrome coronavirus (MERS-CoV), the obvious place to look for the emerging threat was in bats. “Our main goal was to meet with [the] ministry of health, go out to the homes of the patient, and see if he had contact with animals,” says Epstein. “Those are moments when there’s an urgency to understand where diseases are coming from.”

In the forgotten basement of the sand building, the researchers found a colony of 400 to 500 lesser mouse-tailed bats (Rhinopoma hardwickii). “That was our first breakthrough moment,” Epstein recalls. The researchers captured about 60 bats, took blood and urine samples, fecal pellets, and throat swabs, then released the animals unharmed.

I’m confident that MERS does originate in bats. It really appears that this family of viruses has bats as their natural reservoir. —Jon Epstein, EcoHealth Alliance

Buoyed by their discovery of roosting bats in the area, the researchers turned their sights on Bishah, where they found more bat colonies in the town’s abandoned buildings. They returned in April 2013 to collect more evidence, and after catching and working up more than a thousand bats from seven different species, they found a viral RNA fragment in a fecal sample from an Egyptian tomb bat (Taphozous perforatus) that matched the MERS-CoV sequence isolated from the man who had died of the disease months earlier. 2 Although the bat sample yielded only a short stretch of RNA, and scientists are still seeking confirmation with a longer sequence, Epstein says that the initial discovery was important in establishing bats’ role in the MERS epidemic. “I consider this a really strong clue,” he says. “I’m confident that [MERS] does originate in bats. It really appears that this family of viruses has bats as their natural reservoir.” It is not yet clear if bats are directly transmitting MERS to humans or if they play some more nuanced role in the cycle of infection—for example, through interactions with camels, which are also suspected to carry the MERS virus—but Epstein and others are gathering evidence to resolve the picture.

Healthy cauldrons of disease

Mexican free-tailed bats (Tadarida brasiliensis) © POELKING, F./CORBIS MERS, with a fatality rate of around 65 percent, is only one of the deadly diseases that bats have been blamed for transmitting to humans. Researchers have confirmed that the Marburg virus, which causes the particularly gruesome Marburg hemorrhagic fever that killed about 125 people in the Democratic Republic of Congo between 1998 and 2000, resides in the widely distributed African fruit bat (Rousettus aegyptiacus), which likely spread the disease to miners working in the country. 3,4 Ebola, which has infected more than 10,000 and killed nearly 5,000 people during the current outbreak in West Africa, may also have its roots in bats. Amazingly, in most cases, the bats themselves don’t seem to get sick from Ebola, which kills from 25 percent to 90 percent of its human victims, depending on viral strain and treatment availability.

Lesser mouse-tailed bat (Rhinopoma hardwickii) © B.G. THOMSON/SCIENCE SOURCE So, while epidemiologists and health-care workers scramble to help communities being ravaged by emerging disease in the Middle East and Africa, researchers around the world are studying bats’ unique ability to harbor viruses—especially zoonotic viruses that readily cross species boundaries to infect other animals, including humans. Some attribute the high viral diversity associated with bats to the animals’ unique behavior and ecology. And at least one scientist holds that the secret to bats’ virus-hosting capacity lies deep within their cellular machinery.

Recently, Epstein and collaborators, working in Bangladesh, uncovered dozens of viruses that were previously unknown to science circulating in Indian flying foxes (Pteropus giganteus), a bat species known to carry the deadly zoonotic Nipah virus, a member of the paramyxovirus family. 5 And Colleen Webb, an evolutionary ecologist at Colorado State University, determined with collaborators that bats harbor more zoonotic viruses per species than rodents, which carry nasty bugs such as hantavirus and lymphocytic choriomeningitis virus. ' “That’s really the first paper that provides some quantitative evidence that bats are special,” Webb says.

Even to the casual observer, bats are distinctive animals. They are the only mammals that are capable of sustained flight some species possess bizarre facial features to aid in the echolocation they use for hunting and navigation and they often live in massive colonies comprising hundreds of thousands of individuals.

A closer look at bat biology and ecology reveals other traits that set the animals apart. To fuel their daily flight and long migrations, bats have extremely high metabolic rates, which make their bodies frequently mimic a fever-like state. And bats have remarkably long life spans for their body size, giving them plenty of time to be exposed to environmental pathogens. They also roost in large groups that often contain multiple species in tight quarters, setting the stage for pathogen transmission to occur readily and often. “We know that there are these ecological traits that they have that make them theoretically very good at being pathogen reservoirs and spreading diseases,” says Clif McKee, a Colorado State University grad student who studies bacterial pathogens harbored by bats.

Bats’ long evolutionary history may also be at play. Having evolved sometime between 100 million and 66 million years ago, when fearsome dinosaurs ruled the land and pterosaurs patrolled the skies, bats have been battling viral infection and transmission for millennia. “What we’re finding is that bats have had a relatively long-term association with these viruses,” says Epstein. “They come to an understanding over time.” In other words, viruses may have become less threatening but ever-present and easily transmissible commensals of bats.

There’s still a staggering amount of things that we don’t know about bats. —Paul Cryan, US Geological Survey

Answering questions about bat-virus interactions is challenging because bats are extremely difficult research subjects. (See “Experiments on the Wing,” here.) The flying mammals are notoriously hard to keep in captivity, and scientists know surprisingly little about their biology. “Bats are mysterious, and it’s an extremely diverse group of wild animals,” says Paul Cryan, a US Geological Survey bat ecologist who has collaborated with Webb on several bat studies. “There’s still a staggering amount of things that we don’t know about bats.” Given that these animals carry pathogens that have collectively killed thousands of people, that’s a scary thought.

“It wasn’t until very recently that a lot of the interest in viral disease in bats sprung up,” adds Cryan. “The floodgates are now open.”

Learning to fly

Indian flying foxes (Pteropus giganteus) © FLETCHER & BAYLIS/SCIENCE SOURCE The most obvious distinction between bats and other mammals—flight—may hold clues to why bats are so adept at ferrying dangerous pathogens. Evolving the ability to propel their bodies through the air, it seems, has had a strong impact on bat physiology and immunity.

“Flight is very much like fever,” says Tom O’Shea, a US Geological Survey bat biologist in Fort Collins, Colorado. The body temperature of a bat is consistently above normal, which “creates a very different environment in the whole body of a bat compared to any other animal.” From the perspective of viruses, this persistent fever state keeps replication at a lower level than occurs in susceptible animals the virus never overruns the bat’s immune system.

Researchers have also turned up evidence that bats may have less-reactive innate immunity than other mammals. Lin-fa Wang of the Duke–National University of Singapore Graduate Medical School and his collaborators recently sequenced the genomes of two distantly related bats—a fruit bat called the black flying fox (Pteropus alecto) and the insectivorous mouse-eared bat (Myotis davidii)—and found positively selected genes in DNA damage-repair pathways in both species. 7 Wang says that this adaptation was likely spurred, in part, by the energetic and metabolic demands of flight, which can cause DNA damage through the release of reactive oxygen, nitrogen, and carbonyl species. Bats also live 3 to 10 times longer than other mammals of a similar size, giving their genes more time to accumulate mutations. “We believe that [bats] are better at DNA repair because that’s required for their ability to live longer and to fly without too much DNA damage,” Wang says. “Flight drove that evolution.”

Chinese horseshoe bat (Rhinolophus sinicus) © MERLIN D. TUTTLE/SCIENCE SOURCE In the past decade, scientists have uncovered how such changes in their DNA repair pathways can, in turn, affect bats’ innate immune response, possibly allowing the animals to survive with viruses and other resident pathogens. 8 In the two bat species’ genomes, Wang and his team also found positively selected genes in the nuclear factor κB (NF-κB) pathway, which plays roles in transcriptional control, cellular stress responses, and immunity. And the evolutionary timing of these changes, traced using molecular-clock calculations, is telling, says O’Shea. “The genetic adaptations in the innate immune system of bats seem to have changed at about the same time that bats evolved flight.”

Murky territory

Colorized transmission electron micrograph of the Middle East respiratory syndrome coronavirus (MERS-CoV) © SCIENCE SOURCE There are some researchers who are not yet convinced that bats are special with regard to their relationships with zoonotic viruses and other pathogens. “I think the jury is still out on that,” says Peter Daszak, a disease ecologist and president of EcoHealth Alliance, a nonprofit research consortium and conservation group that aims to protect wildlife while safeguarding humans from the emergence of zoonotic disease.

Daszak maintains that while science may show that bats have unique traits that increase their capacity to harbor pathogens, the real reason why bat viruses seem to be spilling over into human populations with increasing regularity is the relationship and proximity between bats and people. “It’s only now, when we’re really starting to encroach in tropical areas, that we’re really coming into contact with bats,” he says. “One possible scenario might be that bats are no more special at harboring viruses than are rodents, but we’ve already come into contact with all the rodent viruses.”

“When we hassle bats or encroach on their habitats, disease is more likely to spill over to us,” Cryan agrees. He adds that there is a danger in broadly painting bats as pathogen ferries on the wing. Despite all the bad press, bats do, after all, provide a multitude of ecosystem services, from pollination and seed dispersal to insect control and plant fertilizer (bats produce scads of nutrient-rich guano), and they constitute an important source of dietary protein in many cultures around the world. 9 Many bat researchers are mindful of the possibility that increased interest in the relationship between viruses and bats could translate into vigilantism against what might be perceived as dangerous animals.

“These are wild animals, and just because they might somehow deal with disease in a special way doesn’t mean they’re bad or evil,” says Cryan. “Bats seem to be able to live with viruses that we consider to be extremely lethal to humans. The advances to human medicine [from studying bats] could be huge, yet those will never happen if the knee-jerk reaction of ‘Kill them all’ manages to prevail.” 

Correction (December 2): Jon Epstein's affiliation was incorrect in the original version of this story. It has been corrected to reflect the fact that he is a veterinary epidemiologist at EcoHealth Alliance. The Scientist regrets the error.

Clarification (December 4): The original version of this story may have given the impression that MERS is transmitted to humans by bats. In fact, the route that the virus has taken to infect humans is not yet clear to researchers, who have gathered substantial evidence that camels in the Middle East also harbor the pathogen that causes MERS. The story has been changed slightly in an attempt to convey this. The Scientist regrets any confusion on this point.

References

  1. X.Y. Ge et al., “Isolation and characterization of a bat SARS-like coronavirus that uses the ACE2 receptor,” Nature, 503:535-38, 2013.
  2. Z.A. Memish et al., “Middle East respiratory syndrome coronavirus in bats, Saudi Arabia,” Emerg Infect Dis, 19:1819-23, 2013.
  3. D.G. Bausch et al., “Marburg hemorrhagic fever associated with multiple genetic lineages of virus,” N Engl J Med, 355:909-19, 2006.
  4. J.S. Towner et al., “Isolation of genetically diverse Marburg viruses from Egyptian fruit bats,” PLOS Pathog, 5:e1000536, 2009.
  5. S.J. Anthony et al., “A strategy to estimate unknown viral diversity in mammals,” M Bio, 4:e00598-13, 2013.
  6. A.D. Luis et al., “A comparison of bats and rodents as reservoirs of zoonotic viruses: are bats special?” Proc Biol Sci, 280:20122753, 2013.
  7. G. Zhang et al., “Comparative analysis of bat genomes provides insight into the evolution of flight and immunity,” Science, 339:456-60, 2013.
  8. G. Chatzinikolaou et al., “DNA damage and innate immunity: links and trade-offs,” Trends in Immunology, 35:429-35, 2014.
  9. T.H. Kunz et al., “Ecosystem services provided by bats,” Ann NY Acad Sci, 1223:1-38, 2011.

© 13/DIGITAL ZOO/OCEAN/CORBIS WHY BATS?

• Flight: Likely in response to the metabolic demands of flight, bats have evolved heightened DNA damage-repair pathways and a high body temperature that mimics a fever state, imparting higher resistance to pathogens.

• Long-lived: With life spans that are 3 to 10 times longer than other mammals of similar size, bats may encounter more pathogens throughout their lives.

• Hibernation: The aggregation of many different bat species in hibernacula during colder months can facilitate the spread of pathogens.

• Colonial: Even during their waking months, some bat species live in remarkably large groups, again facilitating pathogen transmission.

• Evolutionary history: Bats evolved between 100 million and 66 million years ago. They may have established a truce with many bacteria and viruses over the millennia.

EXPERIMENTS ON THE WING

Fruit bats roosting in Kumasi, Ghana COURTESY OF DAVE HAYMAN A scientist striving to know more about a virus or bacterium isolated from bats would likely rely on the traditional methodology of injecting the pathogen into rodent models in the lab to study its pathophysiology and the host’s immune response. But bats appear to have anything but traditional immune systems, putting investigators studying emerging tropical diseases at a disadvantage. “Lab virologists typically don’t have access to the natural host,” says University of Cambridge infectious disease epidemiologist James Wood.

To gain real insights into both the pathogens that infect bats and how the flying mammals cope with such infections, researchers must study—you guessed it—bats. But studying wild bats presents its own challenges: bats tend to live in such massive colonies, and their ranges tend to be so large, that recapturing a particular bat—to check on the persistence of a virus, for example—is virtually impossible.

That’s why, in 2009, Wood and his then–PhD student Dave Hayman decided to start raising a captive colony of bats in Ghana. Along with collaborators, the researchers captured a dozen straw-colored fruit bats (Eidolon helvum), a species widely distributed throughout sub-Saharan Africa. (See photograph at left.) After succeeding in keeping the animals alive for about six months in a roughly 6,000-cubic-meter, double-roofed aviary on the outskirts of Ghana’s capital city, Accra, the team added about three dozen more bats to the colony, now a 100-bat-strong, self-sustaining population. “The beauty of establishing a captive colony is that . . . you know that an individual is exposed to the infections in that colony,” says Hayman, now a disease ecologist at Massey University in New Zealand.

The colony, one of only a few around the world, gives Hayman and his colleagues a unique window onto the bat immune system and the coevolution of bats and their pathogens. “[We’re] trying to understand what we see in the wild, which is a constant, high prevalence of infection,” says Hayman. So far, the researchers who study the captive bats in Ghana have focused on pathogens that were present in the animals when they were captured in the wild and pathogens to which the animals carried antibodies at the time of their capture. These include the Lagos bat virus, henipavirus, and bacteria from the genus Bartonella, to name a few. The team has learned, for example, that henipavirus, a genus that contains the deadly Hendra and Nipah viruses, is capable of persisting in the bat population, with antibody titers ebbing and flowing in female bats through cycles of pregnancy and lactation (J Anim Ecol, 83: 415–28, 2014). Yet the bats don’t seem to die from the viruses, which have spilled over to infect humans and horses in Australia.

We’re trying to understand what we see in the wild, which is a constant, high prevalence of infection. —Dave Hay­man,
Massey University

The team has also discovered that young animals born into the captive bat colony harbor henipaviruses. Researchers used to think that henipavirus infections were immunizing, in the way that flu or measles viruses can be in humans, with virus-specific antibodies able to defend against subsequent attack. In such situations, the persistence of the virus within a population can only be achieved through the introduction of new individuals that have not yet been infected. But the pres­ence of the virus in young bats suggests that the adults are continuously harboring low levels of the pathogen in their cells. While the animals are not sick, they can still pass the virus around. “This work has caused us to rethink the mechanisms of persis­tence of that whole family of viruses within populations of bats,” says Wood.

Eventually the researchers would like to house subgroups of bats in separate enclosures, where the team could expose a subgroup to a new pathogen and follow the dynamics of the disease, Wood says. “We have some facilities in which we could do infection experiments or small-scale transmission experiments in bats.”

“The ultimate aim is to do population-level transmission studies,” Hayman adds. Such research can yield the type of understanding that will help scientists go beyond simply cataloging the different emerging zoonotic diseases that are crossing species boundaries to infect humans, and begin to acquire a functional knowledge of the biology and ecology of bats and the myriad pathogens they host.


Muted immunity

Zhou’s team mimicked infections in the white blood cells of mice and of Chinese rufous horseshoe bats (Rhinolophus sinicus): the species that harboured the SARS virus, which killed almost 600 and infected approaching 7700 during the 2003 outbreak. The mouse cells produced at least 10 times more interferon.

They compared the gene for STING in 30 bat species and 10 flightless mammal species, including humans. In all the bats, STING had lost the amino acid serine at one site, but in all the other mammals STING had kept it. The presence or absence of serine at that site dictated how the cells responded to fake viral infections. By losing the serine, bats tolerate viruses that other mammals would fight off.

“Wild bats may carry viruses for a long time at a low level, less like control and more like coexistence,” says Zhou. “A milder response to viral infection is not always a bad thing.”

“Because some of these viruses may potentially lead to new global pandemics, it’s essential we begin to learn how the bats remain well and unaffected,” says John Mackenzie at Curtin University in Perth, Western Australia.


An international team of researchers used cutting edge technologies to sequence the bats' genome and identify the genes present.

By comparing the blueprint of the bat against 42 other mammals they were able to find out where bats are located within the tree of life.

Bats appear most closely related to a group that consists of carnivores (dogs, cats and seals, among other species), pangolins, whales and ungulates (hooved mammals).

A trawl of genetic differences identified regions of the genome that have evolved differently in bats, which may account for their unique abilities.

The genetic detective work revealed genes that may contribute to echolocation, which bats use to hunt and navigate in complete darkness.


Why do so many deadly viral outbreaks originate in bats?

Ebola, Marburg, SARS, MERS, and now the new coronavirus Covid-19, all share one thing in common – they are thought to have originated in bats. A new study, led by scientists at UC Berkeley, is suggesting the mammals’ uniquely fierce immune system encourages viruses to reproduce and when the viruses cross over into other animals or humans they can be incredibly fatal.

From the frightening hemorrhagic fevers that appeared in the second half of the 20 th century, to the more recent appearances of novel coronaviruses, bats seem to be the natural reservoir for many concerning viral outbreaks. From a perspective of species volume, it is not necessarily a surprise bats are the source of more dangerous viruses than any other mammal.

There are more than 1,400 individual species of bat, spanning almost every corner of the world and comprising around 20 percent of all mammal species. Bats have very few natural predators and live extraordinarily long in relation to their size. Some bats have been found to live up to 40 years.

However, bats are outnumbered by rodents in terms of volume of species and sheer numbers. And while rats certainly spread a number of diseases, they are not generally known for incubating entirely new viruses (rats may have traditionally been blamed for the black plague in medieval Europe but research has shown the real cause of that infamous epidemic was parasites such as fleas and ticks, not rats that carried them).

So what is it about bats that allows them to harbor such virulent viruses without actually getting sick?

"The bottom line is that bats are potentially special when it comes to hosting viruses," says UC Berkeley disease ecologist, and co-author on the new study, Mike Boots. "It is not random that a lot of these viruses are coming from bats. Bats are not even that closely related to us, so we would not expect them to host many human viruses. But this work demonstrates how bat immune systems could drive the virulence that overcomes this."

In order to effectively evolve and spread, a virus can’t kill its host too quickly. The faster a virus replicates and infects a host, the quicker its host will die, so the most effective viruses are the ones than can maintain that precarious balance.

To understand how viruses can evolve in the presence of different mammal immune systems, the new study exposed two different bat cell lines to a hemorrhagic fever virus. A cell line from an African green monkey was also exposed as a control.

The differences between the bat and monkey immune responses were significant. The monkey cell line was rapidly overwhelmed by the replicating virus but the two bat models displayed swift protective immune responses.

The Australian black flying fox cell line demonstrated the most effective immune response to the virus, rapidly producing molecules called interferon-alpha. These immune signaling molecules are released by cells when they are under attack from a foreign substance. They signal to other cells to heighten anti-viral defenses, and actively disrupt viral replication.

What the researchers observed was a distinct slowing of viral replication in the bat cell lines. However, these particular bat interferon responses also allowed the viral infections to persist in the mammals for extended periods of time.

"Think of viruses on a cell monolayer like a fire burning through a forest. Some of the communities – cells – have emergency blankets, and the fire washes through without harming them, but at the end of the day you still have smoldering coals in the system – there are still some viral cells," explains Cara Brook, first author on the new study.

This means a virus can increase its replication rate inside a bat without killing its host, essentially enhancing its virulence to a level that would be profoundly destructive in other organisms.

“This suggests that having a really robust interferon system would help these viruses persist within the host," says Brook. "When you have a higher immune response, you get these cells that are protected from infection, so the virus can actually ramp up its replication rate without causing damage to its host. But when it spills over into something like a human, we don't have those same sorts of antiviral mechanism, and we could experience a lot of pathology."

But why do bats have such fundamentally powerful immune systems?

Intense physical activity in any mammal results in the release of reactive molecules called free radicals. Organisms need to effectively mop up these damaging molecules and the immune system plays a primary role in that process.

Bats, being the world’s only flying mammal, have evolved a remarkably efficient immune system to manage the acute inflammatory damage caused by the high metabolic rate needed to fly. Generally speaking, in mammals fast metabolism and heart rate equals shorter lifespans while slower metabolism and heart rate results in longer lives. Rodents of equivalent size to bats mostly live to ages of two years. Bats on the other hand, can live 30 or 40 years, despite having metabolic rates double that of rats.

It is hypothesized this heightened ability of bats to rapidly suppress inflammation enables the mammal to vigorously fly. And one of the key processes underpinning this rapid anti-inflammatory response is the speedy release of interferon-alpha. Brook notes this enhanced immune response seen in bats would be damaging if replicated within a human body.

"Some bats are able to mount this robust antiviral response, but also balance it with an anti-inflammation response," says Brook. "Our immune system would generate widespread inflammation if attempting this same antiviral strategy. But bats appear uniquely suited to avoiding the threat of immunopathology."

Although this doesn’t explain how the viruses seem to frequently jump from animals to humans, the research does offer compelling insights into how, and why, bats seem to be incubating these incredibly virulent viruses.


Watch the video: Why Do Bats Carry So Many Dangerous Diseases? (October 2022).