Dr Michelle Baker from the CSIRO Australian Animal Health Laboratory spoke at Macquarie University last week about her work on bat immune systems. Her lab recently contributed to the high impact Hendra virus vaccine for horses. Dr Baker’s work has implications for disease control and prevention and management of virus spillovers into human communities worldwide.
Bats make up 20% of mammalian diversity, are long lived for their body size and are the only mammals with powered flight. Bats are vital to ecosystem functions such as pollination, fertilisation and insect control (Calisher et al. 2006). Despite these unique characteristics they are not intensively studied like most other mammal groups. Before Dr Baker’s research group focused on bats not much was known about their immune systems (Baker et al. 2013).
Figure 1. Possible virus transmission routes
(adapted from image presented by Dr Michelle Baker).
Bats act as viral reservoirs, meaning they carry a range of viruses (He et al. 2010; Ng & Baker 2013). Fatal human viruses that can be traced back to bats include Rabies, Hendra, Ebola, Marburg and the SARS coronavirus (Ng & Baker 2013). These viruses occasionally spill over from bats into other animals and that’s normally how humans become infected (Figure 1). But even with this load of up to 100 different viruses, bats are hardly ever sick (Baker et al. 2013).
The bat’s lack of symptoms from viral infections was puzzling, so Dr Baker’s team looked more closely at bat immune systems. When a viral infection occurs in other mammals the immune system quickly delivers a generic response (innate response) and then a specific response occurs more slowly (adaptive response; Katze et al. 2002). The researchers observed that bats don’t develop many antibodies in response to infections, so they thought the bat immune system might be knocking down the viruses before the immune system could mount an adaptive response (Baker et al. 2013).
Figure 2. The Black Flying Fox, Pteropus alecto.
To test this idea the researchers sequenced the genomes and studied the immune responses of two species of bat: Myotis davidii, a micro bat, and Pteropus alecto, a megabat (Figure 2). They found the collection of immune genes in bats is different to other mammals. For example, bats have fewer genes for interferon production (Papenfuss et al. 2012).
Interferon is a protein produced by the immune system in response to the detection of viral invaders. It starts a signaling cascade that creates an anti-viral state in cells (He et al. 2010; Figure 3). High interferon levels can be toxic for cells, so normally the interferon level is very low. When a viral infection is detected, the interferon level is dramatically increased which signals cells to start fighting the infection (Katze et al. 2002). There are multiple types of interferon, but the type Dr Baker spoke most about is interferon alpha (IFNA).
Figure 3. Interferon signaling cascade – causes expression of immune system genes and creates an antiviral state in cells (Katze et al. 2002).
In contrast to expectations, bat cells were found to have their IFNA genes constantly switched on and there is no increase when cells are infected with viruses (Figure 4). Even with this high IFNA level the toxicity effect observed in other mammals isn’t seen in bats. This IFNA level in bats may be part of the reason they can carry so many viruses, but don’t often get sick from them. Other research groups have found that bat IFNA genes have been positively selected which means they must have been beneficial to bats as they lived with viruses in the past (Calisher et al. 2006; He et al. 2010). Recent work has hypothesised that there is a link between the evolution of flight and the ability of bats to harbor viruses without becoming sick (Zhang et al. 2013; O’Shea et al. 2014).
These findings were very new and unexpected so there were lots of questions from the audience after the seminar. It seems like everywhere Dr Baker turned there were more questions! These are the ‘top 5’ questions asked:
- Why aren’t the bats harmed by high levels of interferon in uninfected cells like other mammals?
- What triggers the spillover of viruses into other animals that cause outbreaks?
- Could there be a link between the interferon level and their long lifespan relative to their body size?
- What is the bat immune response to bacterial infection?
- Why doesn’t the bat immune response completely wipe out the viruses? How come the viruses can persist and then spill over into other animals?
Figure 4. Interferon alpha levels in infected and
uninfected cells in bats and other mammals
(adapted from image by Dr Michelle Baker).
So much is currently unknown about how bats can carry so many viruses without being sick. Dr Baker and her team are working to find answers to these questions and more. As human populations increasingly overlap with bat habitats there is more chance of spillover events affecting human and animal populations. Dr Baker’s research could be used to understand human responses to viruses and develop anti-viral treatments in the future.
Baker ML, Schountz T & Wang L-F (2013). Antiviral Immune Responses of Bats: A Review. Zoonoses and Public Health, 60, 104-116. doi: 10.1111/j.1863-2378.2012.01528.x
Calisher CH, Childs JE, Field HE, Holmes KV & Schountz T (2006). Bats: Important Reservoir Hosts of Emerging Viruses. Clinical Microbiology Reviews, 19(3), 531-545. doi: 10.1128/CMR.00017-06
He G, He B, Racey PA & Cui J (2010). Positive Selection of the Bat Interferon Alpha Gene Family. Biochemical Genetics, 48(9-10), 840-846. doi: 10.1007/s10528-010-9365-9
Katze M, He Y & Gale M (2002). Viruses and interferon: A fight for supremacy. Nature Reviews Immunology, 2(9), 675-687. doi: 10.1038/nri888
Ng J & Baker ML (2013). Bats and bat-borne diseases: a perspective on Australian megabats. Australian Journal of Zoology, 61, 48-57. doi: 10.1071/ZO12126
O’Shea T, Cryan P, Cunningham A, Fooks A, Hayman D, Luis A, Peel A, Plowright R, & Wood J (2014). Bat Flight and Zoonotic Viruses. Emerging Infectious Diseases, 20(5), 741-745. doi: 10.3201/eid2005.130539
Papenfuss AT, Baker ML, Feng Z-P, Tachedjian M, Crameri G, Cowled C, Ng J, Janardhana V, Field HE, Wang L-F (2012). The immune gene repertoire of an important viral reservoir, the Australian black flying fox. BMC Genomics, 13:261, doi: 10.1186/1471-2164-13-261.
Zhang G, Cowled C, Shi Z, Huang Z, Bishop-Lilly KA, Fang X, Wynne JW, Xiong Z, Baker ML, Zhao W, Tachedjian M, Zhu Y, Zhou P, Jiang X, Ng J, Yang L, Wu L, Xiao J, Feng Y, Chen Y, Sun X, Zhang Y, Marsh GA, Crameri G, Broder CC, Frey KG, Wang L-F & Wang J (2013). Comparative Analysis of Bat Genomes Provides Insight into the Evolution of Flight and Immunity. Science, 339, 456-460. doi: 10.1126/science.1230835
Silhouette images in Figure 1 sourced from: horse, bat, pig, humans.