Lethal human brain infection by measles virus: phylogeography and mechanisms

病毒学中的一个关键问题是病原体如何适应宿主的不同器官并引起疾病。亚急性硬化性全脑炎（SSPE）是由持续性病毒感染引起的人类中枢神经系统最具特征的疾病之一。它通常发生在急性麻疹病毒（MeV）感染后几年，约1/10000的儿童。SSPE的研究提供了对有利于脑扩散的MeV突变的见解，这种突变在没有病毒颗粒出芽的情况下通过细胞-细胞融合发生。虽然大多数以前的研究仅限于分析单一标本中的病毒RNA，但我们从SSPE患者脑尸检的不同位置获得了标本。我们的试验性深度测序分析，除了揭示所有标本中非常高水平的MeV转录本外，还记录了广泛的基因组多样性。多样性是由于不仅由病毒RNA聚合酶，而且由细胞RNA编辑酶引入的突变。我们已经在编码病毒膜融合器蛋白的基因中鉴定了几个候选的SSPE驱动突变。我们的中心假设是，这些突变中的一些结合起来，通过加速基于细胞的病毒传播而导致致命疾病。我们将（目的1）建立一个时空地图的传播MeV基因组变异在这个大脑中，和（目的2）功能特征的候选SSPE驱动突变的相关性。

A key question in virology is how pathogens adapt to different organs of their hosts, and cause disease. Subacute sclerosing panencephalitis (SSPE) is one of the best characterized diseases of the human central nervous system that is caused by a persistent viral infection. It typically occurs several years after an acute measles virus (MeV) infection, in about 1 in 10’000 children. Studies of SSPE have provided insights into MeV mutations favoring brain spread, which occurs through cell-cell fusion in the absence of virus particle budding. While most previous studies were limited to the analysis of viral RNA in a single specimen, we have obtained specimens from different locations of a SSPE patient brain autopsy. Our pilot deep-sequencing analyses, beside revealing very high levels of MeV transcripts in all specimens, documented extensive genomic diversity. Diversity is due to mutations introduced not only by the viral RNA polymerase, but also by a cellular RNA editing enzyme. We have already identified several candidate SSPE-driver mutations in the genes coding for the viral membrane fusion apparatus proteins. Our central hypothesis is that some of these mutations, in combination, caused lethal disease by accelerating cell-cell based viral spread. We will (aim 1) establish a spatiotemporal map of the spread of MeV genomic variants in this brain, and (aim 2) functionally characterize the relevance of candidate SSPE-driver mutations.