Clayton, Emily and Munir, Muhammad and Unterholzner, Leonie (2024) Investigating the Innate Immune Systems of Bats and Their Roles as Zoonotic Viral Reservoirs. PhD thesis, Lancaster University.
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Abstract
The zoonotic spillover of viral pathogens from wild animal reservoirs into human populations remains the leading cause of emerging and re-emerging infectious diseases globally. Bats represent important viral reservoirs, notorious for the diversity and richness of the viruses they host, several of which are highly pathogenic when transmitted to humans. Remarkably, bats appear to host an abundance of these viruses without exhibiting any clinical signs of disease. A dominant hypothesis for this ability suggests that bats can control viral replication early in the innate immune response, which acts as the first line of defence against infection. However, bat immunology remains fundamentally understudied, largely due to their high species diversity and the lack of accessible reagents required for bat research. Therefore, in this work we explored and characterised key components of bat innate immunity to gain a better understanding of bats as viral reservoirs and contribute to the currently limited literature. Here, we demonstrated the in vitro transcriptomic response of the bat model species, Pteropus alecto (P.alecto) upon stimulation with the bat henipavirus Cedar virus and also with a type III bat interferon (paIFNλ). These investigations highlighted key transcripts, some of which were immune-related, in the response of bats to the separate stimuli and presents a foundation for further research into significant genes concerned in bat viral infection. Building from genome-wide transcriptomics, three distinctive bat innate immune genes representative of different stages of interferon signalling were selected for comparative genomics and functional characterisation. Our work demonstrated the conservation of genes between bats and humans, including IRF7, IFIT5 and IFI35. Specific findings for IRF7 included its successful translocation to the cell nucleus upon stimulation. IFIT5 and IFI35 were specifically selected for exploration due to previous research demonstrating the respective antiviral and conflicting anti- or pro-viral roles of these genes in humans. Significantly, our research demonstrated the direct antiviral action of P.alecto IFIT5 against negative-sense RNA viruses. Collectively, our findings offer valuable contributions to the field of bat antiviral immunity and provide the framework for future investigative studies into the role and function of the bat innate immune system and bat viral tolerance mechanisms.