Key Lab of Animal Epidemiology and Zoonosis, Ministry of Agriculture, National Animal Transmissible Spongiform Encephalopathy Laboratory, College of Veterinary Medicine, China Agricultural University, Beijing, 100093, China; College of Animal and Veterinary Sciences, Southwest Minzu University, Chengdu, 610041, China.
National Center for Tuberculosis Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing, 102206, China.
Vet Microbiol. 2021 Jul;258:109126. doi: 10.1016/j.vetmic.2021.109126. Epub 2021 May 15.
Mycobacterium bovis (M. bovis) infection triggers cytokine production via pattern recognition receptors. These cytokines include type I interferons (IFNs) and interleukin-1β (IL-1β). Excessive type I IFN levels impair host resistance to M. bovis infection. Therefore, strict control of type I IFN production is helpful to reduce pathological damage and bacterial burden. Here, we found that a deficiency in caspase-1, which is the critical component of the inflammasome responsible for IL-1β production, resulted in increased IFN-β production upon M. bovis infection. Subsequent experiments demonstrated that caspase-1 activation reduced cyclic GMP-AMP synthase (cGAS) expression, thereby inhibiting downstream TANK-binding kinase 1 (TBK1)- interferon regulatory factor 3 (IRF3) signaling and ultimately reducing IFN production. A deficiency in caspase-1 activation enhanced the bacterial burden during M. bovis infection in vitro and in vivo and aggravated pathological lesion formation. Thus, caspase-1 activation reduced IFN-β production upon M. bovis infection by dampening cGAS-TBK1-IRF3 signaling, suggesting that the inflammasome protects hosts by negatively regulating harmful cytokines.
牛分枝杆菌（M. bovis）感染通过模式识别受体触发细胞因子的产生。这些细胞因子包括 I 型干扰素（IFN）和白细胞介素-1β（IL-1β）。过多的 I 型 IFN 水平会损害宿主对 M. bovis 感染的抵抗力。因此，严格控制 I 型 IFN 的产生有助于减少病理损伤和细菌负荷。在这里，我们发现，负责 IL-1β 产生的炎症小体的关键组成部分半胱天冬酶-1（caspase-1）缺陷，导致 M. bovis 感染后 IFN-β的产生增加。随后的实验表明，caspase-1 的激活降低了环鸟苷酸-腺苷酸合酶（cGAS）的表达，从而抑制下游 TANK 结合激酶 1（TBK1）-干扰素调节因子 3（IRF3）信号通路，最终减少 IFN 的产生。caspase-1 激活的缺陷增加了体外和体内 M. bovis 感染期间的细菌负荷，并加重了病理损伤的形成。因此，caspase-1 的激活通过抑制 cGAS-TBK1-IRF3 信号通路降低了 M. bovis 感染后的 IFN-β产生，表明炎症小体通过负向调节有害细胞因子来保护宿主。
