Serum Cytokines Predict Neurological Damage in Genetically Diverse Mouse Models.
Serum Cytokines Predict Neurological Damage in Genetically Diverse Mouse Models.
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作者：
病毒感染导致由复杂遗传网络驱动的神经和免疫功能障碍。Theiler的小鼠脑脊髓炎病毒（TMEV）导致小鼠神经功能障碍，并可以模拟人类病毒感染的结果。在这里，我们使用了来自五种协作杂交小鼠品系和C57 BL/6 J的遗传上不同的小鼠来证明TMEV诱导的血清免疫反应如何预测急性感染的神经系统结果。为了检验血清细胞因子水平可以为急性疾病的表型结果提供生物标志物的假设，我们比较了注射前、注射后4天（d.p.i.）和14 d.p.i.每种菌株产生独特的基线细胞因子水平，并对注射程序本身具有不同的免疫应答。因此，我们消除了对注射程序本身的基线反应，并鉴定了由TMEV感染特异性诱导的细胞因子和趋化因子。然后，我们确定了急性疾病期间血清中的菌株特异性纵向细胞因子谱。使用逐步回归分析，我们确定了预测TMEV诱导的急性期神经表型的血清免疫标志物，例如，IL-9用于肢体瘫痪; TNF-α、IL-1β和MIP-1β用于肢体无力。这些发现表明免疫反应的时间差异如何受到宿主遗传背景的影响，并证明血清生物标志物跟踪病毒感染的神经效应的潜力。
Viral infections contribute to neurological and immunological dysfunction driven by complex genetic networks. Theiler’s murine encephalomyelitis virus (TMEV) causes neurological dysfunction in mice and can model human outcomes to viral infections. Here, we used genetically distinct mice from five Collaborative Cross mouse strains and C57BL/6J to demonstrate how TMEV-induced immune responses in serum may predict neurological outcomes in acute infection. To test the hypothesis that serum cytokine levels can provide biomarkers for phenotypic outcomes of acute disease, we compared cytokine levels at pre-injection, 4 days post-injection (d.p.i.), and 14 d.p.i. Each strain produced unique baseline cytokine levels and had distinct immune responses to the injection procedure itself. Thus, we eliminated the baseline responses to the injection procedure itself and identified cytokines and chemokines induced specifically by TMEV infection. Then, we identified strain-specific longitudinal cytokine profiles in serum during acute disease. Using stepwise regression analysis, we identified serum immune markers predictive for TMEV-induced neurological phenotypes of the acute phase, e.g., IL-9 for limb paralysis; and TNF-α, IL-1β, and MIP-1β for limb weakness. These findings indicate how temporal differences in immune responses are influenced by host genetic background and demonstrate the potential of serum biomarkers to track the neurological effects of viral infection.
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