Mechanisms of host resistance and viral tolerance in bats, linking phenotype to genotype
Evolution, Anthropology
Immunology
Final Report Abstract
In the last few years, the occurrence of novel emerging infectious diseases has increased dramatically around the globe. Human activities such as habitat fragmentation, intensified land use and global warming are bringing people into to closer contact with wild animals, facilitating the transmission of bacteria and viruses from animals to humans (zoonosis). Bats are natural carriers (reservoirs) of many zoonotic pathogens, including the potentially deadly Ebola- and henipavirus. Interestingly, bats can harbour most viruses without getting ill, which means that bat-borne viruses can circulate freely in healthy bat populations with the risk of being transmitted to more susceptible species, including humans. At the moment, we don't understand very well why the immune system of bats allows them to co-exist with zoonotic viruses that cause serious disease in other mammals. Improving our knowledge of bat-virus interactions is thus crucial for the development of effective measures to protect humans and animals from zoonosis. In this project I used both experimental and computational methods to identify properties of the bat immune system that allow them to coexist with RNA viruses such as Ebola- and henipavirus. In a first part, I characterised the immune response in different fruit bat species, which received an Ebola or Nipah vaccine simulating a virus infection. I identified several genes and pathways that may determine whether a bat species is a good reservoir of a particular zoonotic virus or not. Most excitingly, I documented a shift towards unspecific (cellular) immunity rather than specific (humoral) immunity during Ebola infection in straw-coloured fruit bats, which likely explains the lack of antibodies and possibly the unsuitability of this species as carrier of Ebola virus. The identified genes and gene networks open up new possibilities for comparative immunological studies in bats as well as in other species that are more susceptible to bat-borne viruses. In the course of these investigations, I made the exciting discovery that some bats in the host lab's captive bat colony never produced antibodies against naturally circulating henipaviruses, suggesting that they have a particular gene variant that make them less susceptible to henipavirus infection. The central immune genes involved in antibody production are organised in a cluster on the genome, the major histocompatibility complex (MHC). MHC genes differ enormously in their DNA sequence between individuals, and are thus prime candidates to explain the observed differences in immune reaction to henipavirus infection. However, we know almost nothing about this important gene complex in bats. In a second part of my project, I thus took this unique chance to characterize the MHC class I region in the straw-coloured fruit bat genome, and identified what we think is the first dominantly expressed classical MHC-I gene described in this species. My results now enable researchers to study individual variation in immunity in Africa's most widespread fruit bat in detail. Understanding the infection dynamics of zoonoses in wild bat populations improve our chances of predicting when and where bat-borne viruses are most likely to spill over from bats to domestic animals and humans. In a third part, I thus assessed the infection dynamics of henipaviruses in Australian fruit bats using mathematical models. I showed that fruit bats most likely harbour latent viral infections that can be reactivated during periods when bats don't find enough food, which are caused by Human-induced landscape and climate changes. These results allow researchers to predict spillovers of deadly henipavirus more precisely in the Australian system, and highlight the importance of conservation efforts to minimize the risk of reactivation of henipavirus infections in bats. To summarize, my project has advanced our knowledge of the adaptive immune response in bats as well as the within-host dynamics driving pulses of zoonotic viruses in reservoir–host populations. My results will help setting up measures to prevent spillover of bat-borne diseases to domestic animals and humans, and could point towards new therapeutic approaches against infections with lethal viruses.
Publications
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Ecology, evolution and spillover of coronaviruses from bats. Nature Reviews Microbiology, 20(5), 299-314.
Ruiz-Aravena, Manuel; McKee, Clifton; Gamble, Amandine; Lunn, Tamika; Morris, Aaron; Snedden, Celine E.; Yinda, Claude Kwe; Port, Julia R.; Buchholz, David W.; Yeo, Yao Yu; Faust, Christina; Jax, Elinor; Dee, Lauren; Jones, Devin N.; Kessler, Maureen K.; Falvo, Caylee; Crowley, Daniel; Bharti, Nita; Brook, Cara E. ... & Plowright, Raina K.
