Gonzalez Victoria, Lobb Briallen, Côté Jacob, Bhuinya Arkadeb, Tubb Adriana G, Nuthalapati Stephen S, Asavajaru Akarin, Zhou Yan, Misra Vikram, Falzarano Darryl, Sweeney Trevor R, Gobeil Sophie M C, Wang Linfa, Doxey Andrew C, Banerjee Arinjay
Laboratory of Zoonotic Viruses and Comparative Immunology, Vaccine and Infectious Disease Organization (VIDO), University of Saskatchewan, Saskatoon, SK, Canada.
Department of Veterinary Microbiology, University of Saskatchewan, Saskatoon, SK, Canada.
Nat Commun. 2025 Jul 1;16(1):5735. doi: 10.1038/s41467-025-61254-7.
Bats are reservoirs of emerging zoonotic viruses that may cause severe disease in humans and agricultural animals. However, it is poorly understood how bats can tolerate diverse viral infections. Here, we characterized type I interferon response pathways in kidney cell lines derived from two divergent bat species, Pteropus alecto and Eptesicus fuscus, identifying distinct mechanisms underlying their enhanced control of viral infection. We demonstrate the critical roles of STAT1/STAT2 in IFNβ signaling, along with species-specific adaptations that contribute towards a steady and ready antiviral state. Unlike in humans, bat IFNβ signaling processes resist the immune antagonistic properties of MERS-CoV which further explains the ability of bats to tolerate coronavirus infections. Transcriptomic analysis on interferon stimulated cell lines identified canonical and non-canonical interferon stimulated genes including two differentially expressed genes, IFIT1 and GBP1, that exhibit enhanced antiviral activity against a wide range of viruses, including the bat-derived Eptesipoxvirus. We have identified a functional (AV1) motif within E. fuscus GBP1 that restricts Eptesipoxvirus replication. Ultimately, our work provides important insights into the evolution of enhanced interferon-mediated antiviral responses in bats, contributing to their ability to resist viral diseases.
蝙蝠是新出现的人畜共患病毒的宿主，这些病毒可能会在人类和农业动物中引发严重疾病。然而，人们对蝙蝠如何耐受多种病毒感染却知之甚少。在此，我们对源自两种不同蝙蝠物种（黑首狐蝠和棕蝠）的肾细胞系中的I型干扰素反应途径进行了表征，确定了它们增强病毒感染控制能力背后的不同机制。我们证明了STAT1/STAT2在IFNβ信号传导中的关键作用，以及有助于形成稳定且随时可用的抗病毒状态的物种特异性适应性变化。与人类不同，蝙蝠的IFNβ信号传导过程能够抵抗中东呼吸综合征冠状病毒的免疫拮抗特性，这进一步解释了蝙蝠耐受冠状病毒感染的能力。对干扰素刺激的细胞系进行的转录组分析确定了经典和非经典的干扰素刺激基因，包括两个差异表达基因IFIT1和GBP1，它们对包括蝙蝠源埃普西病毒在内的多种病毒表现出增强的抗病毒活性。我们在棕蝠GBP1中鉴定出一个功能性（AV1）基序，该基序可限制埃普西病毒的复制。最终，我们的工作为蝙蝠中增强的干扰素介导的抗病毒反应的进化提供了重要见解，有助于它们抵抗病毒性疾病的能力。
