Kulcsar Kirsten A, Baxter Victoria K, Abraham Rachy, Nelson Ashley, Griffin Diane E
Program in Cellular and Molecular Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA W. Harry Feinstone Department of Molecular Microbiology and Immunology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA.
W. Harry Feinstone Department of Molecular Microbiology and Immunology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA.
J Virol. 2015 Aug;89(16):8280-91. doi: 10.1128/JVI.00173-15. Epub 2015 Jun 3.
Susceptibility to alphavirus encephalomyelitis is dependent on a variety of factors, including the genetic background of the host. Neuroadapted Sindbis virus (NSV) causes uniformly fatal disease in adult C57BL/6 (B6) mice, but adult BALB/c (Bc) mice recover from infection. In B6 mice, fatal encephalomyelitis is immune mediated rather than a direct result of virus infection. To identify the immunological determinants of host susceptibility to fatal NSV-induced encephalomyelitis, we compared virus titers and immune responses in adult B6 and Bc mice infected intranasally with NSV. B6 mice had higher levels of virus replication, higher levels of type I interferon (IFN), and slower virus clearance than did Bc mice. B6 mice had more neuronal apoptosis, more severe neurologic disease, and higher mortality than Bc mice. B6 mice had more infiltration of inflammatory cells and higher levels of IL1b, IL-6, TNFa, Csf2, and CCL2 mRNAs and interleukin-6 (IL-6), tumor necrosis factor alpha (TNF-α), IFN-γ, and C-C motif ligand 2 (CCL2) protein in brains than Bc mice. However, Bc mice had more brain antibody at day 7 and a higher percentage of CD4(+) T cells. CD4(+) T cells in the brains of Bc mice included fewer Th17 cells and more regulatory T cells (Tregs) producing IL-10 than B6 mice, accompanied by higher levels of Il2 and Cxcl10 mRNAs. In the absence of IL-10, resistant Bc mice became susceptible to fatal encephalomyelitis after NSV infection. These studies demonstrate the importance of the immune response and its regulation in determining host survival during alphavirus encephalomyelitis.
Mosquito-borne alphavirus infections are an important cause of encephalomyelitis in humans. The severity of disease is dependent both on the strain of the virus and on the age and genetic background of the host. A neurovirulent strain of Sindbis virus causes immune-mediated fatal encephalomyelitis in adult C57BL/6 mice but not in BALB/c mice. To determine the host-dependent immunological mechanisms underlying the differences in susceptibility between these two strains of mice, we compared their immune responses to infection. Resistance to fatal disease in BALB/c mice was associated with better antibody responses, more-rapid virus clearance, fewer Th17 cells, and more-potent regulatory T cell responses than occurred in susceptible C57BL/6 mice. In the absence of interleukin-10, a component of the regulatory immune response, resistant mice became susceptible to lethal disease. This study demonstrates the importance of the immune response and its regulation for host survival during alphavirus encephalomyelitis.
对甲病毒脑脊髓炎的易感性取决于多种因素，包括宿主的遗传背景。神经适应性辛德毕斯病毒（NSV）在成年C57BL/6（B6）小鼠中会引发一致的致命性疾病，但成年BALB/c（Bc）小鼠感染后可恢复。在B6小鼠中，致命性脑脊髓炎是由免疫介导的，而非病毒感染的直接结果。为了确定宿主对致命性NSV诱导的脑脊髓炎易感性的免疫决定因素，我们比较了经鼻感染NSV的成年B6和Bc小鼠的病毒滴度和免疫反应。与Bc小鼠相比，B6小鼠的病毒复制水平更高、I型干扰素（IFN）水平更高，且病毒清除速度更慢。B6小鼠的神经元凋亡更多、神经疾病更严重，死亡率也高于Bc小鼠。与Bc小鼠相比，B6小鼠大脑中的炎性细胞浸润更多，IL1b、IL-6、TNFa、Csf2和CCL2 mRNA以及白细胞介素-6（IL-6）、肿瘤坏死因子α（TNF-α）、IFN-γ和C-C基序配体2（CCL2）蛋白水平更高。然而，Bc小鼠在第7天时脑抗体更多，CD4(+) T细胞百分比更高。与B6小鼠相比，Bc小鼠大脑中的CD4(+) T细胞包括更少的Th17细胞和更多产生IL-10的调节性T细胞（Tregs），同时伴有更高水平的Il2和Cxcl10 mRNA。在缺乏IL-10的情况下，具有抗性的Bc小鼠在感染NSV后变得易患致命性脑脊髓炎。这些研究证明了免疫反应及其调节在决定甲病毒脑脊髓炎期间宿主存活中的重要性。
蚊媒传播的甲病毒感染是人类脑脊髓炎的重要病因。疾病的严重程度既取决于病毒株，也取决于宿主的年龄和遗传背景。一种神经毒力的辛德毕斯病毒株在成年C57BL/6小鼠中会引发免疫介导的致命性脑脊髓炎，但在BALB/c小鼠中则不会。为了确定这两种小鼠品系易感性差异背后的宿主依赖性免疫机制，我们比较了它们对感染的免疫反应。与易感的C57BL/6小鼠相比，BALB/c小鼠对致命疾病的抗性与更好的抗体反应、更快的病毒清除、更少的Th17细胞以及更强的调节性T细胞反应有关。在缺乏调节性免疫反应成分白细胞介素-10的情况下，具有抗性的小鼠变得易患致命性疾病。这项研究证明了免疫反应及其调节在甲病毒脑脊髓炎期间宿主存活中的重要性。
