Photo: iStock.com

Bats are the only mammals that can fly, which is just one of the reasons they fascinate world-class researchers like Bucknell’s DeeAnn Reeder and Ken Field.

Bats have gotten a bad rap lately. A prime suspect as the origin of the coronavirus that causes COVID-19, they’ve taken the blame for this and other diseases that spill over from animals to people. Don’t be so quick to judge these night fliers, however. The same qualities that make bats so good at hosting viruses may also hold the key to fighting COVID-19 in humans. Bats harbor many different coronaviruses, but for some reason, they don’t seem to get sick from them. If scientists can figure out why that is, it might help them develop new therapies for treating COVID-19 and other coronaviruses with the potential to cause future pandemics.

“Bats appear to manage viruses in a different way than other animals do,” says Professor DeeAnn Reeder, biology, who has been studying the flying mammals for more than 20 years. “They appear to be very good at tolerating them, and not dying from them.” She has teamed up with Professor Ken Field, biology chair, for a National Science Foundation- sponsored project to analyze how, on a molecular level, bats have developed that unique tolerance — and whether it might translate to humans.

That tolerance may have something to do with the way bats have evolved, says Field. Some species of bats eat up to their own body weight every night, including thousands of insects, to maintain their energy levels. “Many animals, when they get a viral infection, will huddle down — just like when we have the flu, we want to do nothing but curl up on the couch,” Field says. “But bats have to go out and hunt or forage — if they are not able to eat, they might be too weakened to fight off the infection.”

That mobility may also help explain how viruses spread between bat species and eventually spill over into humans. Viruses such as SARS-CoV-2 (otherwise known as the novel coronavirus) can be transmitted when people encroach into otherwise pristine bat habitats, coming in closer contact with bats than before. Flight may also explain how bats tolerate viruses that are especially virulent in people, as the fever-like elevated temperatures exhibited in bats during flight keep the viruses in check.

The mobility of bats is just one of the qualities that has fascinated Reeder during the decades she’s been studying the animals. “They are the only mammals that really fly, which makes them ecologically and physiologically unique,” she says. “They’re everywhere in the world and just have this incredible diversity. They are amazing.” After arriving in Bucknell in 2005, she established one of the largest research centers in the world for studying active and hibernating bats.

A PRODUCTIVE PARTNERSHIP

Soon afterward, bats in North America began dying from a fungal infection known as white-nose syndrome. Reeder knocked on the door of Field, an expert on comparative immunology, for help in studying the syndrome’s cause. Over the years, the two have developed a highly effective collaboration.

“I’m out in the field collecting the lion’s share of the samples we are using and asking the big questions, and then he somehow figures out how molecularly to answer those questions with his rich perspective on immunology across different species,” says Reeder. “It’s just synergistic.”

When the coronavirus first hit — with its suspected bat connection — Reeder considered how their team could contribute to research on the disease, and immediately thought of the thousands of samples of bat tissue kept in freezers in the basement of the biology building. While many samples were collected in North America, many also came from Africa.

“Some of the work we do requires euthanasia of the animals, and we don’t do that lightly,” Reeder says. To make the most of each procedure, she often freezes samples for future work. “We collect every tissue we possibly can.”

Graduate and undergraduate students frequently join Reeder in Africa to collect those samples, a process that involves stringing 18-meter mist nets in villages to capture fruit bats, which they gingerly extract from the tangle, wearing leather gloves. “It was definitely tedious and required a sharp focus so you didn’t hurt yourself or cause any extra trauma to the bats,” says Jordan Simpson M’21, a graduate student who accompanied Reeder to Uganda in 2018.

For Simpson it was a transformative experience to conduct field research in Africa and collaborate with local scientists who conduct vital research on diseases with comparatively few resources. “It was really humbling to see that and made me fall in love with fieldwork even more,” says Simpson, whose thesis examines potential immune-system gene responses to stressors such as parasitic infection. “I wanted to help educate people and raise up other budding scientists.”

A RAPID RESPONSE

After the bats are collected, they are humanely euthanized and dissected to remove certain organs, which are frozen with liquid nitrogen for transport to the freezers at Bucknell. Unlike in humans, where coronavirus primarily infects the lungs, bats tend to carry the virus in their intestines. Reeder and Field found they had plenty of intestinal samples from bats from both continents to examine for the NSF project, which is supported by money Congress allocated under the CARES Act to provide coronavirus relief. Within two weeks of submitting an application for a Rapid Response Research Into COVID project, the researchers received a $200,000 grant — a process that usually takes six months or more. “They weren’t kidding when they called it rapid,” Field says.

The biologists will use the tissue samples to investigate what enables bats to live with coronaviruses, including those related to SARS-CoV2. “Many people who die of COVID-19 are dying because of immunopathology — their immune systems are overreacting,” Reeder says. When a person becomes infected, she explains, their immune systems must perform a delicate balance, ramping up enough to fight off the infection, but putting on the brakes before causing harm to one’s own body.

“Those ‘brakes’ seem to be missing in the people who are getting very sick and dying,” Reeder says. “It’s probably not that they don’t have them, but sometimes the pathogens can be really sneaky and disable that braking system.” During a typical infection, cells produce chemicals known as cytokines to influence neighboring cells, including a class known as interferons, which heighten inflammation to bring more white blood cells to attack the virus.

In severe COVID-19, however, the body produces too many interferons, leading to a so-called cytokine storm. Excessive inflammation ensues, causing fluid buildup in the lungs — and then suffocation. “We want to know how bats can manage this infection without ever having their responses go haywire,” Reeder says.

The investigators plan to sequence the entire genome of every coronavirus they find in samples from as many as 200 different bats. They’ll also use a tool called transcriptomics, which can detect RNA created from the expression of different genes in the bat host cells. By examining which RNA is produced in response to which coronaviruses, they hope to determine which genes are being activated in response to the infection.

RESEARCHER GOES BATTY

To assist this project, Field and Reeder have hired researcher Sara Talmage to extract the samples. She’ll thaw the tissues and break them down to remove their component parts, separating RNA from protein and DNA so it can be analyzed. “I’m new to the bat world,” Talmage says, “but it’s an exciting time to be doing this kind of research, and to see how bats control these diseases that humans have been unable to control.”

An outside company will do the actual sequencing of the RNA, which will return terabytes of data in the form of billions of letters that represent genetic code. Undergraduate researchers Isabel Steinberg ’23 and Morgan Thomas ’23 will use bioinformatic approaches to identify which genetic pathways are getting switched on and off in the different samples.

Thomas, a cell biology/biochemistry major, is excited to learn and apply these cutting-edge techniques. “Being able to analyze this data, I think, will be valuable in going into industry later,” she says. “It’s incredible to think about how our research and experiments in the lab can contribute to important discoveries that could ultimately be used to develop a treatment.”

The first step toward solving that mystery will be to discover which coronaviruses have infected the bats sampled. The main varieties are alpha coronaviruses, which cause the common cold and are generally mild in humans, and beta coronaviruses, which cause much more serious infections, such as SARS, MERS and COVID-19. While African bats are often infected with both viruses, North American bats are only infected with the former. “We expect to find both alpha and beta coronaviruses in African bats, but only alpha coronaviruses in the North American bats,” Field says.

Field hypothesizes that comparing the bats’ immune responses to the alpha and beta coronaviruses may reveal a particular genetic response that helps protect the bats from a cytokine storm — the same sort that can wreak havoc on humans responding to the more serious viruses. That could take one of two forms, he says. “One is that the bats don’t turn on the inflammatory pathway that, when activated, causes all of the damage,” says Field. “They’ve co-evolved with these viruses for so long that they’ve lost the ability to respond to them in a way that is harmful.”

BLOCKING THE DAMAGE

The other possibility is more intriguing — instead of a missing pathway, the bats may have alterations in a different pathway that actually blocks the damage and prevents inflammation. “There are pathways that are going awry in human cases,” says Reeder, “and if we have comparative data from bats that shows these pathways are getting shut off because different genes are involved, then we may be able to see where the brakes are.”

That, in turn, could help eventually develop drugs — or drug cocktails combining multiple drugs — that can recreate this bat-like response in humans. Says Reeder, “By identifying where these brakes are, we can basically say to the biomedical folks, ‘Look at what we found,’ and they can say, ‘Well, maybe this class of drugs would work best to dampen things.’ ”

At present, doctors treating COVID are forced to use powerful drugs such as corticosteroids to reduce the inflammatory response. Those are blunt instruments that block many different pathways at once, says Field. “So it might be preferable to have a more finely tuned target.” While such a therapeutic will likely take years to develop, the findings from the Bucknell study could help create treatments for future pandemics — as global warming and habitat destruction will inevitably lead to more disease transmission from bats to humans.

“We are in an era of pandemics, and there will probably be more viruses in this particular lineage,” Reeder says. “In reality, there’s going to be a COVID-25 or COVID-30. So anything we find will, I think, inform the field going forward on how to manage these things.”

Field and Reeder are hoping to receive funding soon for another study that would involve traveling back to Africa and challenging bats with virus particle vaccines to study the intricacies of their immune response. While all of the research they conduct is worthwhile, they say, they are especially grateful to have found themselves in the right place with the right tools to potentially contribute on an issue of such global significance.

“Basic science fills a gap and is always really valuable,” says Reeder, “but every now and then there is an opportunity for your data to be really important because of what is happening in the world. It’s amazing to be able to significantly contribute to the understanding of what is going on with these viruses.”