Dampened NLRP3-mediated inflammation in bats and implications for a special viral reservoir host

• Published in: Nature microbiology Vol. 4; no. 5; pp. 789 - 799
• Main Authors: Ahn, Matae, Anderson, Danielle E., Zhang, Qian, Tan, Chee Wah, Lim, Beng Lee, Luko, Katarina, Wen, Ming, Chia, Wan Ni, Mani, Shailendra, Wang, Loo Chien, Ng, Justin Han Jia, Sobota, Radoslaw M., Dutertre, Charles-Antoine, Ginhoux, Florent, Shi, Zheng-Li, Irving, Aaron T., Wang, Lin-Fa
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.05.2019; Nature Publishing Group
• Subjects: 13/1; 13/106; 13/109; 13/31; 14/19; 14/34; 14/35; 14/63; 38; 38/39; 38/77; 38/91; 631/250/255/2514; 631/250/256/2177; 631/326/596/2564; 82/29; 82/58; 82/80; 82/83; Age; Alternative splicing; Animals; Apoptosis; Biomedical and Life Sciences; Cell activation; Chiroptera; Chiroptera - genetics; Chiroptera - immunology; Chiroptera - virology; Coronaviridae; Coronavirus Infections - immunology; Coronavirus Infections - virology; Coronaviruses; Disease Reservoirs - virology; Double-stranded RNA; Humans; IL-1β; Infectious Diseases; Inflammasomes; Inflammasomes - chemistry; Inflammasomes - genetics; Inflammasomes - immunology; Inflammation; Influenza A; Influenza A virus - genetics; Influenza A virus - immunology; Influenza, Human - genetics; Influenza, Human - immunology; Influenza, Human - virology; Interleukin-1beta - genetics; Interleukin-1beta - immunology; Leucine; Life Sciences; Medical Microbiology; Metabolic rate; Mice; Microbiology; Middle East Respiratory Syndrome Coronavirus - genetics; Middle East Respiratory Syndrome Coronavirus - immunology; NLR Family, Pyrin Domain-Containing 3 Protein - chemistry; NLR Family, Pyrin Domain-Containing 3 Protein - genetics; NLR Family, Pyrin Domain-Containing 3 Protein - immunology; Parasitology; Protein Domains; Pyrin protein; RNA viruses; Transcription; Transcription activation; Virology; Viruses; Zoonoses
• ISSN: 2058-5276
• DOI: 10.1038/s41564-019-0371-3

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. Dampened activation of the NLR family pyrin domain containing 3 (NLRP3) inflammasome in bat primary immune cells in response to infection with multiple zoonotic viruses is caused by decreased transcriptional priming, the presence of a unique splice variant and an altered leucine-rich repeat domain of bat NLRP3.