Department of Clinical Neuroscience, Neuroimmunology Unit, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.
PLoS Pathog. 2012;8(6):e1002753. doi: 10.1371/journal.ppat.1002753. Epub 2012 Jun 28.
Herpes simplex encephalitis (HSE) is a fatal infection of the central nervous system (CNS) predominantly caused by Herpes simplex virus type 1. Factors regulating the susceptibility to HSE are still largely unknown. To identify host gene(s) regulating HSE susceptibility we performed a genome-wide linkage scan in an intercross between the susceptible DA and the resistant PVG rat. We found one major quantitative trait locus (QTL), Hse1, on rat chromosome 4 (confidence interval 24.3-31 Mb; LOD score 29.5) governing disease susceptibility. Fine mapping of Hse1 using recombinants, haplotype mapping and sequencing, as well as expression analysis of all genes in the interval identified the calcitonin receptor gene (Calcr) as the main candidate, which also is supported by functional studies. Thus, using unbiased genetic approach variability in Calcr was identified as potentially critical for infection and viral spread to the CNS and subsequent HSE development.
单纯疱疹脑炎（HSE）是一种中枢神经系统（CNS）的致命感染，主要由单纯疱疹病毒 1 型引起。调节 HSE 易感性的因素在很大程度上仍不清楚。为了确定调节 HSE 易感性的宿主基因，我们在易感 DA 和抗性 PVG 大鼠的杂交后代中进行了全基因组连锁扫描。我们在大鼠染色体 4 上发现了一个主要的数量性状基因座（QTL）Hse1，该基因座控制疾病易感性（置信区间 24.3-31 Mb；LOD 评分 29.5）。使用重组体、单倍型图谱和测序对 Hse1 进行精细作图，以及对该区间内所有基因的表达分析，确定降钙素受体基因（Calcr）是主要候选基因，这也得到了功能研究的支持。因此，使用无偏遗传方法，Calcr 的变异性被确定为感染和病毒向中枢神经系统传播以及随后发生 HSE 的关键因素。
