National Key Laboratory of Agricultural Microbiology, Huazhong Agricultural University, Wuhan 430070, China; Hubei Hongshan Laboratory, Wuhan 430070, China; Key Laboratory of Preventive Veterinary Medicine of Hubei Province, Huazhong Agricultural University, Wuhan 430070, China.
National Key Laboratory of Agricultural Microbiology, Huazhong Agricultural University, Wuhan 430070, China; Key Laboratory of Preventive Veterinary Medicine of Hubei Province, Huazhong Agricultural University, Wuhan 430070, China.
Cell Rep. 2024 Jul 23;43(7):114478. doi: 10.1016/j.celrep.2024.114478. Epub 2024 Jul 9.
Lyssavirus is a kind of neurotropic pathogen that needs to evade peripheral host immunity to enter the central nervous system to accomplish infection. NLRP3 inflammasome activation is essential for the host to defend against pathogen invasion. This study demonstrates that the matrix protein (M) of lyssavirus can inhibit both the priming step and the activation step of NLRP3 inflammasome activation. Specifically, M of lyssavirus can compete with NEK7 for binding to NLRP3, which restricts downstream apoptosis-associated speck-like protein containing a CARD (ASC) oligomerization. The serine amino acid at the 158th site of M among lyssavirus is critical for restricting ASC oligomerization. Moreover, recombinant lab-attenuated lyssavirus rabies (rabies lyssavirus [RABV]) with G158S mutation at M decreases interleukin-1β (IL-1β) production in bone-marrow-derived dendritic cells (BMDCs) to facilitate lyssavirus invasion into the brain thereby elevating pathogenicity in mice. Taken together, this study reveals a common mechanism by which lyssavirus inhibits NLRP3 inflammasome activation to evade host defenses.
狂犬病毒是一种嗜神经病原体，需要逃避外周宿主免疫以进入中枢神经系统来完成感染。NLRP3 炎性小体的激活对于宿主抵御病原体入侵至关重要。本研究表明，狂犬病毒的基质蛋白 (M) 可以抑制 NLRP3 炎性小体激活的引发步骤和激活步骤。具体而言，狂犬病毒的 M 可以与 NEK7 竞争结合 NLRP3，从而限制下游凋亡相关斑点样蛋白包含一个 CARD（ASC）寡聚化。狂犬病毒 M 中的第 158 位丝氨酸氨基酸对于限制 ASC 寡聚化至关重要。此外，在 M 中具有 G158S 突变的重组实验室减毒狂犬病毒（狂犬病病毒 [RABV]）降低了骨髓来源的树突状细胞（BMDCs）中白细胞介素-1β（IL-1β）的产生，从而促进了狂犬病毒侵入大脑，从而提高了小鼠的致病性。总之，本研究揭示了狂犬病毒抑制 NLRP3 炎性小体激活以逃避宿主防御的共同机制。
