Why do bats play host to so many viruses?

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).

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