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Abstract Bats carry viruses that can cause severe disease in other mammals. Asymptomatic infections in bats suggest limited tissue-damaging inflammation and immunopathology. To investigate the genomic basis of disease resistance, the Bat1K project generated reference-quality genomes of ten bat species. A systematic analysis showed that signatures of selection in immune genes are more prevalent in bats compared with other mammals. We found an excess of immune gene adaptations in the ancestral Chiroptera and many descending bat lineages, highlighting viral entry and detection factors, and regulators of antiviral and inflammatory responses. ISG15, an antiviral gene contributing to hyperinflammation during COVID-19, exhibits a deletion of a cysteine, required for homodimer formation, in rhinolophid and hipposiderid bats. Cellular infection experiments showed enhanced intracellular protein conjugation of bat ISG15 and lack of secretion into extracellular space, where human ISG15 stimulates inflammation. Our work highlights molecular mechanisms contributing to viral tolerance and disease resistance in bats.
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This content will become publicly available on February 13, 2026
Bat genomes illuminate adaptations to viral tolerance and disease resistance
Zoonoses are infectious diseases transmitted from animals to humans. Bats have been suggested to harbour more zoonotic viruses than any other mammalian order1. Infections in bats are largely asymptomatic2,3, indicating limited tissue-damaging inflammation and immunopathology. To investigate the genomic basis of disease resistance, the Bat1K project generated reference-quality genomes of ten bat species, including potential viral reservoirs. Here we describe a systematic analysis covering 115 mammalian genomes that revealed that signatures of selection in immune genes are more prevalent in bats than in other mammalian orders. We found an excess of immune gene adaptations in the ancestral chiropteran branch and in many descending bat lineages, highlighting viral entry and detection factors, and regulators of antiviral and inflammatory responses. ISG15, which is an antiviral gene contributing to hyperinflammation during COVID-19 (refs. 4,5), exhibits key residue changes in rhinolophid and hipposiderid bats. Cellular infection experiments show species- specific antiviral differences and an essential role of protein conjugation in antiviral function of bat ISG15, separate from its role in secretion and inflammation in humans. Furthermore, in contrast to humans, ISG15 in most rhinolophid and hipposiderid bats has strong anti-SARS-CoV-2 activity. Our work reveals molecular mechanisms that contribute to viral tolerance and disease resistance in bats.
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- PAR ID:
- 10643429
- Author(s) / Creator(s):
- ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; more »
- Publisher / Repository:
- Springer Nature
- Date Published:
- Journal Name:
- Nature
- Volume:
- 638
- Issue:
- 8050
- ISSN:
- 0028-0836
- Page Range / eLocation ID:
- 449 to 458
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
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