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Interleukin-10 Modulation of Virus Clearance and Disease in Mice with Alphaviral Encephalomyelitis
Journal of Virology ( IF 4.0 ) Pub Date : 2018-03-15 , DOI: 10.1128/jvi.01517-17
Nina M Martin 1 , Diane E Griffin 2
Affiliation  

Alphaviruses are an important cause of mosquito-borne outbreaks of arthritis, rash, and encephalomyelitis. Previous studies in mice with a virulent strain (neuroadapted SINV [NSV]) of the alphavirus Sindbis virus (SINV) identified a role for Th17 cells and regulation by interleukin-10 (IL-10) in the pathogenesis of fatal encephalomyelitis (K. A. Kulcsar, V. K. Baxter, I. P. Greene, and D. E. Griffin, Proc Natl Acad Sci U S A 111:16053–16058, 2014, https://doi.org/10.1073/pnas.1418966111). To determine the role of virus virulence in generation of immune responses, we analyzed the modulatory effects of IL-10 on disease severity, virus clearance, and the CD4+ T cell response to infection with a recombinant strain of SINV of intermediate virulence (TE12). The absence of IL-10 during TE12 infection led to longer morbidity, more weight loss, higher mortality, and slower viral clearance than in wild-type mice. More severe disease and impaired virus clearance in IL-10−/− mice were associated with more Th1 cells, fewer Th2 cells, innate lymphoid type 2 cells, regulatory cells, and B cells, and delayed production of antiviral antibody in the central nervous system (CNS) without an effect on Th17 cells. Therefore, IL-10 deficiency led to more severe disease in TE12-infected mice by increasing Th1 cells and by hampering development of the local B cell responses necessary for rapid production of antiviral antibody and virus clearance from the CNS. In addition, the shift from Th17 to Th1 responses with decreased virus virulence indicates that the effects of IL-10 deficiency on immunopathologic responses in the CNS during alphavirus infection are influenced by virus strain.

IMPORTANCE Alphaviruses cause mosquito-borne outbreaks of encephalomyelitis, but determinants of outcome are incompletely understood. We analyzed the effects of the anti-inflammatory cytokine IL-10 on disease severity and virus clearance after infection with an alphavirus strain of intermediate virulence. The absence of IL-10 led to longer illness, more weight loss, more death, and slower viral clearance than in mice that produced IL-10. IL-10 influenced development of disease-causing T cells and entry into the brain of B cells producing antiviral antibody. The Th1 pathogenic cell subtype that developed in IL-10-deficient mice infected with a less virulent virus was distinct from the Th17 subtype that developed in response to a more virulent virus, indicating a role for virus strain in determining the immune response. Slow production of antibody in the nervous system led to delayed virus clearance. Therefore, both the virus strain and the host response to infection are important determinants of outcome.



中文翻译:


IL-10 对甲型病毒性脑脊髓炎小鼠病毒清除和疾病的调节



甲病毒是蚊媒关节炎、皮疹和脑脊髓炎爆发的重要原因。先前对携带甲病毒辛德比斯病毒 (SINV) 强毒株(神经适应性 SINV [NSV])的小鼠进行的研究确定了 Th17 细胞和白细胞介素 10 (IL-10) 的调节在致命性脑脊髓炎发病机制中的作用 (KA Kulcsar, VK Baxter、IP Greene 和 DE Griffin,Proc Natl Acad Sci USA 111:16053–16058,2014,https://doi.org/10.1073/pnas.1418966111)。为了确定病毒毒力在免疫反应产生中的作用,我们分析了 IL-10 对疾病严重程度、病毒清除以及 CD4 + T 细胞对中毒力 SINV 重组株 (TE12) 感染的反应的调节作用。 。与野生型小鼠相比,TE12感染期间IL-10的缺失导致发病时间更长、体重减轻更多、死亡率更高以及病毒清除速度更慢。 IL-10 −/−小鼠中更严重的疾病和病毒清除受损与更多的 Th1 细胞、更少的 Th2 细胞、先天淋巴 2 型细胞、调节细胞和 B 细胞以及中枢神经系统中抗病毒抗体的延迟产生有关(CNS) 对 Th17 细胞没有影响。因此,IL-10缺乏通过增加Th1细胞并阻碍快速产生抗病毒抗体和中枢神经系统清除病毒所必需的局部B细胞反应,导致TE12感染小鼠出现更严重的疾病。此外,随着病毒毒力降低,从 Th17 反应转向 Th1 反应表明,甲病毒感染期间 IL-10 缺乏对中枢神经系统免疫病理反应的影响受到病毒株的影响。


重要性甲病毒引起蚊媒脑脊髓炎的爆发,但结果的决定因素尚不完全清楚。我们分析了中毒力甲病毒株感染后抗炎细胞因子 IL-10 对疾病严重程度和病毒清除的影响。与产生 IL-10 的小鼠相比,缺乏 IL-10 会导致患病时间更长、体重减轻更多、死亡更多、病毒清除速度更慢。 IL-10 影响致病 T 细胞的发育以及产生抗病毒抗体的 B 细胞进入大脑。在感染弱毒力病毒的 IL-10 缺陷小鼠中发育的 Th1 致病细胞亚型与响应强毒力病毒而发育的 Th17 亚型不同,这表明病毒株在决定免疫反应中的作用。神经系统中抗体产生缓慢导致病毒清除延迟。因此,病毒株和宿主对感染的反应都是结果的重要决定因素。

更新日期:2018-02-27
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