Bats have been a fascinating enigma for scientists for many decades. In various experiments, it has been found that when bats are infected with deadly viruses—such as Marburg virus or SARS-like viruses—they develop an active infection and the virus replicates in their bodies, yet they remain completely healthy, showing no signs of disease. This amazing ability allows them to serve as a natural reservoir for pathogenic viruses such as coronaviruses (including SARS‑CoV‑2, the cause of COVID‑19) and Ebola [1]. These viruses are capable of killing other mammals, yet they have almost no effect on bats. Groundbreaking research has recently revealed the complex genetic and molecular mechanisms underlying this impressive immunity.

A large international research team, led by Dr. Ariadna Morales and Prof. Michael Hiller from Goethe University (Frankfurt) and researchers from the BAT1K project (which aims to sequence the genomes of all bat species in the world – over 1,400 species), has completed an extensive study comparing the immune systems of bats to those of other mammals. The study [2], published in the prestigious journal Nature, revealed not only individual adaptations but an entire system of advanced changes in the immune system that evolved over tens of millions of years.

Initially, the researchers examined the prevalence of various viruses in bats. They found that among all the viruses detected in bats, the proportion of viruses from the coronavirus family (which are very well known) is significantly higher than that found in other mammals. While only 1.4% of the viruses detected in rodents are coronaviruses, in bats they constitute 17.8% of all viruses. An even more astounding figure was found in horseshoe bats (named after the shape of their nose, which resembles a horseshoe) and their relatives, the Rhinolophidae and Hipposideridae families. In these groups, over 40% and 30% (respectively) of the viruses detected are coronaviruses.

This finding led the team to focus on these bat families. Using advanced DNA sequencing technologies, the researchers created detailed genetic maps of ten carefully selected key species. When they compared their genomes to those of 105 other bats and mammals, they discovered something remarkable: using advanced statistical methods that examine the ratio of protein-altering mutations to “silent” mutations (which do not change protein sequences), the researchers demonstrated that in bats, the genes related to the immune system underwent extensive evolution—more so than any other group of mammals.

It turned out that the timing of these changes is particularly interesting: many key immune adaptations appeared in the common ancestor of all bats, around the time when the ability to fly developed in bats. Flight requires an extremely high metabolic rate. Such metabolism produces numerous byproducts that stimulate the immune system and cause “sterile” inflammation (inflammation not caused by an infection). Therefore, the researchers hypothesized that bats’ unique ability to cope with viruses evolved as a secondary adaptation—a by‑product of the need to regulate the inflammation caused by flight itself. Apparently, a sophisticated immune system comes at a very high energetic cost, which explains why it did not develop in a similar way in other mammals.

Previous studies have already shown that while severe viral infections in humans sometimes cause damage due to an overreaction of the immune system (“cytokine storm” [3]), bats have evolved multiple mechanisms that prevent such dangerous inflammation while still enabling them to fight viruses effectively.

In the current study, the research team identified several key genes involved in this balanced response. Some improve the early detection of viruses, allowing for a rapid initial response. Other genes help to suppress inflammation once the threat is under control. This two‑step approach enables bats to combat viruses without causing collateral damage to their tissues.

One of the most prominent discoveries in the study concerns a protein called ISG15. This protein is usually secreted in large quantities in the presence of a viral infection and has two main roles: within the cell, it binds to many proteins and inhibits viral replication, and outside the cell, it promotes inflammatory processes. In horseshoe bats and their close relatives, this protein underwent a unique change—a deletion of a specific amino acid (cysteine‑78). This change prevents the protein from forming dimers, thereby enhancing its antiviral activity within the cell while reducing its inflammatory effect outside the cell.

When ISG15 from different sources (humans and bats) was tested against various viruses, several key findings emerged. When cells were infected with SARS‑CoV‑2, the human-derived ISG15 had only a modest effect. In contrast, the ISG15 protein from most horseshoe bats and their relatives reduced viral replication in cells by 80%–90%. This strong antiviral effect depends on the protein’s ability to bind to other cellular proteins, a process known as ISGylation.

Additionally, the researchers discovered that bats have developed unique changes in several of the key regulatory proteins of the immune system. For example, the protein TRIM38 plays a dual role in their immune response: in the early stages of viral infection, it enhances the initial immune response by preventing the degradation of viral recognition proteins, and in the later stages of infection, it helps suppress inflammation. This temporal regulation allows bats to mount a strong early antiviral response and, as a result, prevent the development of excessive inflammation.

Moreover, the researchers uncovered a complex network of inflammation control mechanisms unique to bats. They found that bats have lost certain genes that promote inflammation. Among other things, the IL36A gene is absent already in the common ancestor of several bat families, and in horseshoe bats specifically, the IL36G gene is not present.

The researchers also found changes in genes such as BTK, which contributes both to the initial immune response and to the activation of the inflammasome (a protein complex responsible for initiating the immune response). In humans, BTK is essential for inflammasome activation, and its inhibition has been shown to reduce excessive inflammation in severe COVID‑19 cases. It appears that in bats, a version of BTK has evolved that helps dampen the inflammasome response while maintaining its positive functions in the immune system.

These mechanisms form part of the complex immune balance (which humans generally struggle to achieve), enabling bats to fight viruses effectively while preventing excessive inflammation—a capability described above that distinguishes their immune system. These findings, along with other adaptations identified in genes related to DNA repair, metabolism, and aging, provide a glimpse into a unique world of immune evolution. The implications for human medicine could be significant, as understanding the immune balance of bats may lead to the development of new treatment strategies aimed at preventing or mitigating harmful inflammation once it begins.

This groundbreaking study highlights how understanding nature’s biological solutions can contribute to medical science and to addressing future viral threats.

Yomiran is a member of the research team.

Image: Greater mouse-tailed bats (Rhinopoma microphyllum), whose genome was studied in this research. Photo: Eran Amichai.

Hebrew Editing: Smadar Raban
English Editing: Elee Shimshoni

Sources and further reading

[1] Article about inflammation, viruses and bats (Hebrew)

[2] The original research paper from Nature

[3] Article about cytokine storm (Hebrew)

[4] “TalkingScience” Podcast Episode 22: Shaked Ashkenazi on the Great Invasion (Hebrew)

[5] “TalkingScience” Podcast Episode 81: Expert Panel on Bats (Hebrew)