Bats are special in their ability to host emerging viruses. As the only flying mammal, bats endure high metabolic rates yet exhibit elongated lifespans. It is currently unclear whether these unique features are interlinked. The important inflammasome sensor, NLR family pyrin domain containing 3 (NLRP3), has been linked to both viral-induced and age-related inflammation. Here, we report significantly dampened activation of the NLRP3 inflammasome in bat primary immune cells compared to human or mouse counterparts. Lower induction of apoptosis-associated speck-like protein containing a CARD (ASC) speck formation and secretion of interleukin-1β in response to both ‘sterile’ stimuli and infection with multiple zoonotic viruses including influenza A virus (−single-stranded (ss) RNA), Melaka virus (PRV3M, double-stranded RNA) and Middle East respiratory syndrome coronavirus (+ssRNA) was observed. Importantly, this reduction of inflammation had no impact on the overall viral loads. We identified dampened transcriptional priming, a novel splice variant and an altered leucine-rich repeat domain of bat NLRP3 as the cause. Our results elucidate an important mechanism through which bats dampen inflammation with implications for longevity and unique viral reservoir status.
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The data supporting the findings of this study are available from the corresponding authors upon request. RNA–seq data used in this study have been deposited in the NCBI Sequence Read Archive (SRR8382151). The bat NLRP3 sequences generated in this study have been deposited in GenBank under accession numbers MK355440–MK355443. Supplementary figures and tables are provided in the Supplementary Information.
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This work was funded by the Singapore National Research Foundation (grants NRF2012NRF-CRP001–056 to F.G. and L.-F.W. and NRF2016NRF-NSFC002–013 to L.-F.W.), a New Investigator’s Grant (to A.T.I.) from the National Medical Research Council of Singapore (NMRC/BNIG/2040/2015) and the National Natural Science Foundation of China (31621061). R.M.S. is supported by a Young Investigator Grant YIG 2015 (BMRC, A*STAR) and NMRC MS-CETSA platform grant (MOHIAFCAT2/004/2015). The authors thank the following for help with bat sampling: Crameri Research Consulting, J. Meers, H. Field and Duke-NUS team members (for a detailed listing see Supplementary Information). The authors thank A. Bertoletti and A. T. Tan for use of the Amnis ImageStream. The authors give special thanks to E. Latz for providing the immortalized NLRP3-knockout macrophages. The authors also acknowledge the facilities and technical assistance of the Advanced Bioimaging Core and Flow Cytometry Core at SingHealth Duke-NUS Academic Medical Centre, and X. F. Lim and S. Velraj for their valuable assistance in the Duke-NUS ABSL3 Facility.
The authors declare no competing interests.
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