Genetic and immunological contributors to virus-induced paralysis.
Genetic and immunological contributors to virus-induced paralysis.
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DOI：
10.1016/j.bbih.2021.100395
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发表时间：
2021-12
期刊：
影响因子：
--
通讯作者：
Brinkmeyer-Langford C
中科院分区：
文献类型：
--
作者：
Perez Gomez AA;Karmakar M;Carroll RJ;Lawley KS;Amstalden K;Young CR;Threadgill DW;Welsh CJ;Brinkmeyer-Langford C
单一病毒的感染可以引起不同的免疫反应，导致不同的神经系统结果，这取决于宿主的遗传背景。为了研究异质性病毒应答，我们使用Theiler小鼠脑脊髓炎病毒（TMEV）在协作杂交（CC）小鼠中模拟病毒诱导的神经表型和免疫应答。CC资源由遗传上不同的和可重复的小鼠品系组成，从而提供了具有类似于人类的遗传异质性的群体模型。我们通过测量23种不同细胞因子和趋化因子的血清水平，研究了不同CC株在感染后90天（dpi）内慢性期TMEV诱导的免疫应答对神经系统结局的影响，特别关注肢体瘫痪。无论是否存在TMEV RNA，每种CC毒株均表现出一组独特的免疫应答。使用逐步回归，确定了IL-1α、RANTES和瘫痪频率评分之间的显著相关性。为了更好地理解这些相互作用，我们评估了不同CC遗传背景的多个方面，包括先前与TMEV发病机制和病毒清除或持久性相关的基因组区域的单倍型，个体细胞因子水平和TMEV相关基因表达。这些结果表明，以前与TMEV结果相关的基因座如何提供关于CC株中TMEV诱导的瘫痪的不完整信息。总的来说，这些发现提供了深入了解免疫反应在受宿主遗传背景影响的病毒相关神经系统疾病发病机制中的复杂作用。TMEV长期感染导致的瘫痪因宿主遗传背景而异。对于CC小鼠，没有单一的免疫环境导致TMEV感染后瘫痪。IL-1A和RANTES显著影响瘫痪随时间的进展。H2单倍型不能单独预测病毒的存在或TMEV诱导的瘫痪。瘫痪的严重程度受到多个TMEV和免疫相关基因座的影响。
Infection by a single virus can evoke diverse immune responses, resulting in different neurological outcomes, depending on the host's genetic background. To study heterogenous viral response, we use Theiler's Murine Encephalomyelitis Virus (TMEV) to model virally induced neurological phenotypes and immune responses in Collaborative Cross (CC) mice. The CC resource consists of genetically distinct and reproducible mouse lines, thus providing a population model with genetic heterogeneity similar to humans. We examined different CC strains for the effect of chronic stage TMEV-induced immune responses on neurological outcomes throughout 90 days post infection (dpi), with a particular focus on limb paralysis, by measuring serum levels of 23 different cytokines and chemokines. Each CC strain demonstrated a unique set of immune responses, regardless of presence or absence of TMEV RNA. Using stepwise regression, significant associations were identified between IL-1α, RANTES, and paralysis frequency scores. To better understand these interactions, we evaluated multiple aspects of the different CC genetic backgrounds, including haplotypes of genomic regions previously linked with TMEV pathogenesis and viral clearance or persistence, individual cytokine levels, and TMEV-relevant gene expression. These results demonstrate how loci previously associated with TMEV outcomes provide incomplete information regarding TMEV-induced paralysis in the CC strains. Overall, these findings provide insight into the complex roles of immune response in the pathogenesis of virus-associated neurological diseases influenced by host genetic background. Paralysis resulting from long-term TMEV infection varies by host genetic background. For CC mice, no single immune environment causes paralysis following TMEV infection. IL-1A and RANTES significantly influence the progression of paralysis over time. H2 haplotype alone did not predict viral presence or TMEV-induced paralysis. Paralysis severity is influenced by multiple TMEV- and immune-related loci.
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影响因子：
2.4
作者：
Glabinski, AR;Tuohy, VK;Ransohoff, RM
通讯作者：
Ransohoff, RM
影响因子：
64.5
作者：
Gomez JA;Wapinski OL;Yang YW;Bureau JF;Gopinath S;Monack DM;Chang HY;Brahic M;Kirkegaard K
通讯作者：
Kirkegaard K
影响因子：
3.7
作者：
Glabinski, AR;Bielecki, B;Ransohoff, RM
通讯作者：
Ransohoff, RM
影响因子：
3.7
作者：
Chang, JR;Zaczynska, E;Oleszak, EL
通讯作者：
Oleszak, EL
影响因子：
4.6
作者：
Bijalwan, M.;Young, C. R.;Welsh, C. J.
通讯作者：
Welsh, C. J.