埃博拉病毒(EBOV)导致一种称为埃博拉病毒病(EVD)的严重感染。EBOV感染的发病机制复杂,结果与多种免疫和细胞因子有关。疾病可以由几种机制引起,包括病毒复制导致的直接器官和内皮细胞损伤。在2013年至2016年西非EBOV爆发期间,出现了几个突变体,随着核蛋白(NP)基因的变化,糖蛋白(GP),和大(L)蛋白质。反向遗传分析已用于研究这些突变是否在发病机理中起任何作用,结果参差不齐,具体取决于所用的实验系统。以前的研究调查了三个单一的非同义突变(GP-A82V,NP-R111C,和L-D759G)对小鼠和雪貂模型的死亡率,并表明L-D759G突变降低了EBOV的毒力。在这项研究中,通过深度测序进一步评估这三种突变的影响,以确定病毒群体遗传学和纵向血液样本中的宿主反应,肝脏,肾,脾,脾和取自先前雪貂模型的肺组织。数据表明,突变维持在不同的组织中,但是微小基因组突变的频率不同。此外,与野生型病毒相比,重组突变体在宿主内具有不同的效应,其中L蛋白中的D759G(和伴随的Q986H)取代导致肾脏中免疫反应的上调,肝脏,脾,脾还有肺.这些研究一起提供了对宿主之间和宿主内部EBOV突变体生物学的见解。重要性埃博拉病毒感染会对人体产生巨大影响,这在埃博拉病毒病中表现出来。感染的结果是生存或死亡,在前一组中,可能会造成长期健康后果和持续感染。疾病的严重程度无疑与宿主反应有关,通常有明显的炎症反应与较差的结局相关。2013年至2016年西非埃博拉病毒爆发的规模揭示了病毒生物学的新方面。这包括具有潜在改变的毒力的突变体的出现。来自西非爆发中出现的感染了不同突变体的EBOV雪貂模型的生物样本组织用于研究不同组织中EBOV基因组变异的影响。总的来说,这项工作提供了对EBOV群体遗传学的见解,并表明动物模型中的不同器官对EBOV变体的反应不同。
Ebola virus (EBOV) causes a severe infection called Ebola virus disease (EVD). The pathogenesis of EBOV infection is complex, and outcome has been associated with a variety of immunological and cellular factors. Disease can result from several mechanisms, including direct organ and endothelial cell damage as a result of viral replication. During the2013 to 2016 Western Africa EBOV outbreak, several mutants emerged, with changes in the genes of nucleoprotein (NP), glycoprotein (GP), and the large (L) protein. Reverse genetic analysis has been used to investigate whether these mutations played any role in pathogenesis with mixed results depending on the experimental system used. Previous studies investigated the impact of three single nonsynonymous mutations (GP-A82V, NP-R111C, and L-D759G) on the fatality rate of mouse and ferret models and suggested that the L-D759G mutation decreased the virulence of EBOV. In this study, the effect of these three mutations was further evaluated by deep sequencing to determine viral population genetics and the host response in longitudinal samples of blood, liver, kidney, spleen, and lung tissues taken from the previous ferret model. The data indicated that the mutations were maintained in the different tissues, but the frequency of minor genomic mutations were different. In addition, compared to wild-type virus, the recombinant mutants had different within host effects, where the D759G (and accompanying Q986H) substitution in the L protein resulted in an upregulation of the immune response in the kidney, liver, spleen, and lungs. Together these studies provide insights into the biology of EBOV mutants both between and within hosts. IMPORTANCE Ebola virus infection can have dramatic effects on the human body which manifest in Ebola virus disease. The outcome of infection is either survival or death and in the former group with the potential of longer-term health consequences and persistent infection. Disease severity is undoubtedly associated with the host response, often with overt inflammatory responses correlated with poorer outcomes. The scale of the2013 to 2016 Western African Ebola virus outbreak revealed new aspects of viral biology. This included the emergence of mutants with potentially altered virulence. Biobanked tissue from ferret models of EBOV infected with different mutants that emerged in the Western Africa outbreak was used to investigate the effect of EBOV genomic variation in different tissues. Overall, the work provided insights into the population genetics of EBOV and showed that different organs in an animal model can respond differently to variants of EBOV.