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Why Do Bats Play Host To So Many Viruses?

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Bats can play host to many viruses, genomic analyses are starting to uncover why

Bats harbor many viruses that can spill over into humans, including Marburg, Ebola, and famously SARS-CoV-2. But while these viruses often cause severe illness in humans, they do not appear to hamper bats. A new study offers a clue to why bats can tolerate so many viruses that can be fatal to humans.

Researchers led by Michael Hiller at the LOEWE Centre for Translational and Biodiversity Genomics and Aaron T. Irving at Zhejiang University found that bats have more immune system modifications compared with other mammals. (Nature 2025, DOI: 10.1038/s41586-024-08471-0).

The researchers performed comprehensive genome sequencing on 10 bat species that are known reservoirs of zoonotic viruses. Comparing the sequences with those of 115 other mammal species, they found that bats display immune signatures not found in other mammals.

The group paid particular attention to the gene for the protein ISG15. This protein plays a role in the inflammatory response to a SARS-CoV-2 infection and is associated with the hyperinflammation that accompanies worse outcomes for patients. In bats, the researchers found that a cysteine amino acid was deleted, affecting the protein's ability to form dimers, which is the form thought to act as a cytokine outside the cell, according to the researchers. In bats, there is some evidence that ISG15 may not cause hyperinflammation, but this is not definitive.

"We think that [bats'] ISG15 is essentially tuned to work well against coronaviruses," Hiller says.

But according to Hiller, this deletion is not the clear cause behind ISG15's altered function in bats. Irving's team created ISG15 proteins with the cysteine in bat cells, as well as versions of the protein with a deleted or mutated cysteine in human cells.

While the researchers did confirm that the cysteine was required for the proteins to dimerize, "the ability to suppress viral production changed in an unpredictable way," Hiller says. "We couldn't say every time you have a cysteine, you're more potent, or if you mutate the cysteine, you're less potent."

One hypothesis is that having these immune system modifications is evolutionarily favorable to the bats, who need to control inflammation caused by high metabolic activity during flight, Hiller says. That activity can damage macromolecules, leading to inflammation, and so it is reasonable that bats would evolve methods of controlling that inflammation.

In an accompanying article discussing the new findings, Junji Zhu and Michaela Gack from the Cleveland Clinic's Florida Research and Innovation Center, who were not involved with the research, say that "decoding bats' viral disease resistance will be crucial for mitigating future pandemics caused by 'spillover' events in which viruses are transmitted from animals to humans." (Nature 2025, DOI: 10.1038/d41586-025-00081-8).

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"It will also provide valuable insights to aid the design of therapeutic strategies for human disorders that are driven by overactive inflammation," they add.

How Flight Helped Bats Become Invincible To Viruses

Bats produce harmful chemicals while flying, which might have driven them to evolve resistance to viruses.Credit: Marko König/imageBROKER via Alamy

Bats' ability to swoop and soar through the sky might have given them another 'superpower' — invincibility to most viruses.

Around the time that bat ancestors evolved powered flight, their genomes picked up immune adaptations that can quell viral infections, finds a study of 20 bat genomes, including of species that carry the coronaviruses most closely related to SARS-CoV-2.

Bats — the only flying mammals — are suspected or known reservoirs for a horde of deadly viruses, including rabies, Ebola, Marburg and SARS-related viruses, which circulate in horseshoe bats (Rhinolophus) in southeast Asia. Field and laboratory studies suggest that bats rarely become ill from these viruses and don't mount the harmful immune overreactions seen, for instance, in people with severe COVID-19.

"There's something unique about bats," says Aaron Irving, a comparative immunologist at the Zhejiang University–University of Edinburgh Institute in Haining, China, who co-led the study, published1 on 29 January in Nature. "When they are infected, generally, they're quite healthy. They somehow evolved the right way to control their immune responses without going overboard."

To uncover secrets to bat immunity, a team led by Irving and Michael Hiller, an evolutionary genomicist at the Senckenberg Research Institute in Frankfurt, Germany, sequenced the genomes of ten bats, including four horseshoe bat and three species part of a family called hipposiderids, all of which are coronavirus reservoirs. The researchers then analysed these along with ten previously sequenced bat species from other parts of the family tree.

Compared with 95 other mammal species, bats had especially high numbers of immune genes, with changes indicative of natural selection. Some of these alterations were limited to individual branches of the bat family tree, hinting that they evolved after the group began diversifying. But many immune adaptations were shared by all bats, suggesting that they emerged in a common ancestor of all bats — and at around the same point that fossil evidence has suggested that powered flight evolved in the animals.

The Hunt Narrows For Ebolavirus Hosts

Bats are widely recognized as the primary hosts of filoviruses, such as Ebola, yet the specific host species of ebolaviruses are not definitively known. In a study led by the University of California, Davis, and the Albert Einstein College of Medicine (Einstein), scientists have developed a new tool to narrow down potential host species of filoviruses and better prioritize wildlife surveillance. The research is part of global efforts to prevent viral spillover between animals and humans.

The study, published today in the journal Cell Host & Microbe, sheds light on the molecular rules that govern how filoviruses recognize their receptor and helps pinpoint unknown hosts of these viruses.

"The fundamental question is, where is the next ebolavirus outbreak going to come from?" said co-leading author Simon Anthony, an associate professor with the UC Davis School of Veterinary Medicine. "If we don't know what the wildlife host is, we can't know how, where or when that will be."

The biggest filovirus outbreak, caused by Ebola virus, occurred in three West African countries from 2014 to 2016. It killed more than 11,000 people and infected more than 28,000. More recently, a filovirus outbreak caused by Marburg virus began last September in Rwanda, resulting in at least 15 deaths and 66 cases.

Unlocking the cell

The study is the most comprehensive investigation of filovirus receptor binding in bats to date. To enter a human cell, an ebolavirus glycoprotein has to attach — or bind — to a cell receptor.

In 2011, co-leading author Kartik Chandran, professor of microbiology and immunology at Einstein, helped discover the cholesterol-trafficking protein Niemann-Pick C1 (NPC1) as this critical Ebola entry receptor.

"Remarkably, all filoviruses isolated to date require NPC1 as a receptor," said Chandran.

For this study, the authors conducted large-scale binding assays to evaluate how well the glycoprotein from different filoviruses interact with bat NPC1 proteins. They also used machine learning to decipher the genetic code underpinning receptor binding for these viruses.

The researchers then focused on bat species whose NPC1 proteins bind strongly to the Ebola virus glycoprotein and live in regions where previous Ebola outbreaks have occurred. This helps narrow down which bat species have a high potential to host the virus.

"To me, this is putting together two beautiful pieces of the puzzle that are seemingly unrelated — geographic information and molecular data — all to solve the question of, will these bats be able to host the virus or not?" said co-leading author Gorka Lasso, a research assistant professor at Einstein.

Guiding future surveillance

This work can guide future surveillance efforts to identify the host reservoir of Ebola virus and other related viruses. As new ebolaviruses and variants are discovered, scientists can also use this method to assess their potential for infecting humans.

"Hopefully this will light the path forward, not just for filoviruses but for other viruses, as well," said Lasso.

The research was inspired in part by a 2015 study by Chandran that revealed that African straw-colored fruit bats were seemingly resistant to Ebola virus infection. The Ebola virus binded poorly to straw-colored fruit bats' NPC1 receptor.

"That really struck me," said Anthony, who helped discover the sixth known ebolavirus strain, Bombali virus. "It became clear that there are some species that cannot be the host because they cannot be infected. Having information about which species are and are not more likely to be the host reservoir is information we should have."

This study was funded through U.S. Agency for International Development, National Institutes of Health, and National Science Foundation's Predictive Intelligence for Pandemic Prevention.

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