He Sheng, Zhu Yanyan, Wang Xinyue, Zhang Gaofeng, Hou Kaijian, Xia Xianzhu, Jiang Zhenyou, Gong Xiaoqian, Zhao Pingsen
Department of Laboratory Medicine, Yuebei People's Hospital, Affiliated to Shantou University Medical College, Shaoguan, 512025, China.
Laboratory for Diagnosis of Clinical Microbiology and Infection, Yuebei People's Hospital, Affiliated to Shantou University Medical College, Shaoguan, 512025, China.
J Neuroinflammation. 2025 Apr 20;22(1):113. doi: 10.1186/s12974-025-03423-5.
Viral encephalitis, resulting from neurotropic viral infections, leads to severe neurological impairment, inflammation, and exhibits high mortality rates with poor prognosis. Currently, there is a lack of effective targeted treatments for this disease, which poses a significant public health concern. SARM1 has been identified as the pivotal mediator of axonal degeneration and inflammation across various neuropathies, activated by an elevation in the NMN/NAD ratio. However, comprehensive in vivo investigations into the role of SARM1-mediated pathogenesis in viral encephalitis are still lacking. In this study, we established mouse models of viral encephalitis using Japanese encephalitis virus (JEV), herpes simplex virus-1 (HSV-1), and rabies virus (RABV) as representative pathogens. Our findings demonstrate that neurotropic virus infections elicit robust axonal degeneration, mitochondrial dysfunction, and profound neuropathological damage in cortical neurons via the activation of SARM1. In mouse models of viral encephalitis, deletion or inhibition of SARM1 effectively preserved axonal morphology and maintained mitochondrial homeostasis, while also attenuating the infiltration of CD45 leukocytes in the cortex. Consequently, these interventions ameliorated neuropathological damage and enhanced survival outcomes in mice. Our findings suggest that SARM1-mediated axonal degeneration and brain inflammation exacerbate the pathological progression of viral encephalitis. Therapies targeting SARM1 emerge as viable and promising strategies for protecting neuronal function in the context of neurotropic viral infections.
病毒性脑炎由嗜神经病毒感染引起，会导致严重的神经功能障碍、炎症，且死亡率高、预后差。目前，针对这种疾病缺乏有效的靶向治疗方法，这引起了重大的公共卫生问题。SARM1已被确定为各种神经病变中轴突退化和炎症的关键介质，由NMN/NAD比值升高激活。然而，目前仍缺乏对SARM1介导的发病机制在病毒性脑炎中作用的全面体内研究。在本研究中，我们使用日本脑炎病毒（JEV）、单纯疱疹病毒1型（HSV-1）和狂犬病病毒（RABV）作为代表性病原体，建立了病毒性脑炎小鼠模型。我们的研究结果表明，嗜神经病毒感染通过激活SARM1，在皮质神经元中引发强烈的轴突退化、线粒体功能障碍和严重的神经病理损伤。在病毒性脑炎小鼠模型中，删除或抑制SARM1可有效保留轴突形态并维持线粒体稳态，同时还可减少皮质中CD45白细胞的浸润。因此，这些干预措施改善了神经病理损伤并提高了小鼠的存活结果。我们的研究结果表明，SARM1介导的轴突退化和脑部炎症会加剧病毒性脑炎的病理进展。针对SARM1的疗法成为在嗜神经病毒感染情况下保护神经元功能的可行且有前景的策略。
