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The secret to bats' immunity

2020.06.28

An international research team led by Duke-NUS Medical School, Singapore, has identified molecular and genetic mechanisms that allow bats to stay healthy while hosting viruses that kill other animals, according to a new study published in the journal Nature Microbiology.

Bats live very long and host numerous viruses, such as Ebola virus, Nipah virus, and severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS) coronaviruses, that are extremely harmful when they infect humans and other animals. Researchers at Duke-NUS Medical School and colleagues wanted to find out how bats can harbour so many of these pathogens without suffering from diseases.

The key, they found, is in the bat's ability to limit inflammation. Bats do not react to infection with the typical inflammatory response that often leads to pathological damage. In humans, while the inflammatory response helps fight infection when properly controlled, it has also been shown to contribute to the damage caused by infectious diseases, as well as to aging and age-related diseases when it goes into overdrive.

The researchers found that the inflammation sensor that normally triggers the body's response to fight off stress and infection, a protein called NLRP3, barely reacts in bats compared to humans and mice, even in the presence of high viral loads.

"Bats' natural ability to dampen inflammation caused by stress and infection may be a key mechanism underlying their long lifespans and unique viral reservoir status," said Dr Matae Ahn, first author of the study and an MD-PhD candidate of the Emerging Infectious Diseases (EID) Programme at Duke-NUS Medical School.

The researchers compared the responses of immune cells from bats, mice and humans to three different RNA viruses -- influenza A virus, MERS coronavirus, and Melaka virus. The inflammation mediated by NLRP3 was significantly reduced in bats compared to mice and humans.

Digging further, they found that 'transcriptional priming', a key step in the process to make NLRP3 proteins, was reduced in bats compared with mice and humans. They also found unique variants of NLRP3 only present in bats that render the proteins less active in bats than in other species. These variations were observed in two very distinct species of bats -- Pteropus alecto, a large fruit bat known as the Black Flying Fox, and Myotis davadii, a tiny vesper bat from China -- indicating that they have been genetically conserved through evolution. Further analysis comparing 10 bat and 17 non-bat mammalian NLRP3 gene sequences confirmed that these adaptations appear to be bat-specific.

What this implies, the researchers explain, is that rather than having a better ability to fight infection, bats have a much higher tolerance for it. The dampening of the inflammatory response actually enables them to survive.

"Bats appear to be capable of limiting excessive or inappropriate virus-induced inflammation, which often leads to severe diseases in other infected animals and people," said Professor Wang Lin-Fa, Director of Duke-NUS' EID Programme and senior author of the study. "Our finding may provide lessons for controlling human infectious diseases by shifting the focus from the traditional specific anti-pathogen approach to the broader anti-disease approach successfully adopted by bats."

Professor Patrick Casey, Duke-NUS Medical School's Vice Dean for Research, noted of the findings: "With this study, our researchers have advanced our understanding of an area that had long remained a mystery. This is yet another example of the world-class research and global collaboration that is a hallmark of Duke-NUS."

There's Something Special About Bat Immunity That Makes Them Ideal Viral Incubators

Ebola. SARS. Rabies. MERS. Most probably even the flourishing new coronavirus, COVID-19. There's one animal that innocently and unwittingly gifts all these virulent scourges to humanity. Bats.

Why is that? According to new research, it's because bats may be the ultimate incubator, courtesy of a fiercely effective and robust immune system that seems to, in effect, train up viral strains, encouraging them to adapt and evolve into becoming as fit and infectious as they possibly can.

It's an unfortunate side effect of what is otherwise an awesome survival mechanism. Not unfortunate for bats, that is, but certainly for other species – because when viruses manage to leap from bats to other sorts of animals, including humans, the recipients' immune responses aren't equipped to counter these attuned, efficient, and highly transmissible pathogens.

"The bottom line is that bats are potentially special when it comes to hosting viruses," says disease ecologist Mike Boots from UC Berkeley.

"It is not random that a lot of these viruses are coming from bats."

In a new study, Boots and fellow researchers investigated virus infectivity on bat cell lines, including cultures from the Egyptian fruit bat (Rousettus aegyptiacus) and the Australian black flying fox (Pteropus alecto).

Cells called Vero cells from a monkey (the African green monkey, Chlorocebus), were also used as a control, but these monkey cells were at a definite disadvantage.

That's because one of the molecular mechanisms in bats' immune systems is the lightning fast production of a signalling molecule called interferon-alpha, which is triggered in the response of viruses. When interferon proteins are secreted by virus-infected cells, nearby cells go into a defensive, antiviral state.

The African green monkey cell line does not possess such advantages. In experiments, when the cell cultures were exposed to viruses mimicking Ebola and Marburg virus, the monkey cells were quickly overwhelmed. The bat cells, on the other hand, resisted the viral onslaught, thanks to their rapid interferon signalling.

The paradox, though, is that interferon ultimately seems to benefit viruses, even while it hinders their capacity to kill cells. While the signalling system prevents cells from dying, the infection nonetheless holds on, and the virus starts to adapt to the defensive regime, at least according to the team's computer simulations.

"This suggests that having a really robust interferon system would help these viruses persist within the host," says biologist and first author of the study, Cara 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."

It's important to note that humans do have interferon-alpha, but bats seem to have a much easier time with viruses than we do.

Even when bats are infected with pathogens that can kill humans, they don't demonstrate obvious disease symptoms, but instead carry viruses as long-term persistent infections. That persistence, the researchers say, seems to be encouraged by interferon.

More research is needed to investigate why bat interferon systems seem to be more robust and faster than ours.

"Critically, we found that bat cell lines demonstrated a signature of enhanced interferon-mediated immune response … which allowed for establishment of rapid within-host, cell-to-cell virus transmission rates," the authors explain in their study.

"The antiviral state induced by the interferon pathway protects live cells from mortality in tissue culture, resulting in in vitro epidemics of extended duration that enhance that probability of establishing a long-term persistent infection."

The upshot, the team says, is that rapidly replicating viruses that have evolved within bats will probably cause enhanced virulence if they jump to subsequent hosts, including humans, with immune systems that diverge from those unique to bats.

Sometimes an intermediary is involved, like pigs, camels, or horses. Whichever animal is unlucky enough to be a spillover host, though, it's unlikely they'll be ready for the fate that awaits them.

Nonetheless, knowing how and why this happens is vital to fighting these viruses, no matter how formidable their training, gleaned inside the invulnerable bodies of bats, may have made them.

"It is really important to understand the trajectory of an infection in order to be able to predict emergence and spread and transmission," Brook says.

The findings are reported in eLife.

Source: ScienceDaily, ScienceAlert!