Pappalardo Morena, Juliá Miguel, Howard Mark J, Rossman Jeremy S, Michaelis Martin, Wass Mark N
Centre for Molecular Processing and School of Biosciences, University of Kent, Canterbury, Kent CT2 7NJ, UK.
Sci Rep. 2016 Mar 24;6:23743. doi: 10.1038/srep23743.
Reston viruses are the only Ebolaviruses that are not pathogenic in humans. We analyzed 196 Ebolavirus genomes and identified specificity determining positions (SDPs) in all nine Ebolavirus proteins that distinguish Reston viruses from the four human pathogenic Ebolaviruses. A subset of these SDPs will explain the differences in human pathogenicity between Reston and the other four ebolavirus species. Structural analysis was performed to identify those SDPs that are likely to have a functional effect. This analysis revealed novel functional insights in particular for Ebolavirus proteins VP40 and VP24. The VP40 SDP P85T interferes with VP40 function by altering octamer formation. The VP40 SDP Q245P affects the structure and hydrophobic core of the protein and consequently protein function. Three VP24 SDPs (T131S, M136L, Q139R) are likely to impair VP24 binding to human karyopherin alpha5 (KPNA5) and therefore inhibition of interferon signaling. Since VP24 is critical for Ebolavirus adaptation to novel hosts, and only a few SDPs distinguish Reston virus VP24 from VP24 of other Ebolaviruses, human pathogenic Reston viruses may emerge. This is of concern since Reston viruses circulate in domestic pigs and can infect humans, possibly via airborne transmission.
雷斯顿病毒是唯一对人类无致病性的埃博拉病毒。我们分析了196个埃博拉病毒基因组，并在所有9种埃博拉病毒蛋白中确定了特异性决定位点（SDPs），这些位点可将雷斯顿病毒与四种人类致病性埃博拉病毒区分开来。这些SDPs的一个子集将解释雷斯顿病毒与其他四种埃博拉病毒在人类致病性上的差异。进行了结构分析以确定那些可能具有功能影响的SDPs。该分析揭示了特别是对于埃博拉病毒蛋白VP40和VP24的新功能见解。VP40的SDP P85T通过改变八聚体形成来干扰VP40功能。VP40的SDP Q245P影响该蛋白的结构和疏水核心，从而影响蛋白功能。三个VP24的SDPs（T131S、M136L、Q139R）可能会损害VP24与人核转运蛋白α5（KPNA5）的结合，进而抑制干扰素信号传导。由于VP24对埃博拉病毒适应新宿主至关重要，并且只有少数SDPs将雷斯顿病毒的VP24与其他埃博拉病毒的VP24区分开来，因此可能会出现具有人类致病性的雷斯顿病毒。这令人担忧，因为雷斯顿病毒在家猪中传播，并且可能通过空气传播感染人类。
