Department of Molecular Biology and Biochemistry, School of Biological Sciences, University of California, Irvine, Irvine, California, USA.
Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, Texas, USA.
J Virol. 2020 May 18;94(11). doi: 10.1128/JVI.00250-20.
Ebola virus (EBOV) continues to pose a significant threat to human health, as evidenced by the 2013-2016 epidemic in West Africa and the ongoing outbreak in the Democratic Republic of the Congo. EBOV causes hemorrhagic fever, organ damage, and shock culminating in death, with case fatality rates as high as 90%. This high lethality combined with the paucity of licensed medical countermeasures makes EBOV a critical human pathogen. Although EBOV infection results in significant damage to the liver and the adrenal glands, little is known about the molecular signatures of injury in these organs. Moreover, while changes in peripheral blood cells are becoming increasingly understood, the host responses within organs and lymphoid tissues remain poorly characterized. To address this knowledge gap, we tracked longitudinal transcriptional changes in tissues collected from EBOV-Makona-infected cynomolgus macaques. Following infection, both liver and adrenal glands exhibited significant and early downregulation of genes involved in metabolism, coagulation, hormone synthesis, and angiogenesis; upregulated genes were associated with inflammation. Analysis of lymphoid tissues showed early upregulation of genes that play a role in innate immunity and inflammation and downregulation of genes associated with cell cycle and adaptive immunity. Moreover, transient activation of innate immune responses and downregulation of humoral immune responses in lymphoid tissues were confirmed with flow cytometry. Together, these data suggest that the liver, adrenal gland, and lymphatic organs are important sites of EBOV infection and that dysregulating the function of these vital organs contributes to the development of Ebola virus disease. Ebola virus (EBOV) remains a high-priority pathogen since it continues to cause outbreaks with high case fatality rates. Although it is well established that EBOV results in severe organ damage, our understanding of tissue injury in the liver, adrenal glands, and lymphoid tissues remains limited. We begin to address this knowledge gap by conducting longitudinal gene expression studies in these tissues, which were collected from EBOV-infected cynomolgus macaques. We report robust and early gene expression changes within these tissues, indicating they are primary sites of EBOV infection. Furthermore, genes involved in metabolism, coagulation, and adaptive immunity were downregulated, while inflammation-related genes were upregulated. These results indicate significant tissue damage consistent with the development of hemorrhagic fever and lymphopenia. Our study provides novel insight into EBOV-host interactions and elucidates how host responses within the liver, adrenal glands, and lymphoid tissues contribute to EBOV pathogenesis.
埃博拉病毒（EBOV）继续对人类健康构成重大威胁，这一点从 2013 年至 2016 年西非的疫情和刚果民主共和国正在发生的疫情中可见一斑。EBOV 引起出血热、器官损伤和休克，最终导致死亡，病死率高达 90%。这种高致死率加上缺乏许可的医疗对策，使得 EBOV 成为一种重要的人类病原体。尽管 EBOV 感染会对肝脏和肾上腺造成严重损害，但人们对这些器官损伤的分子特征知之甚少。此外，虽然外周血细胞的变化越来越被理解，但器官和淋巴组织内的宿主反应仍未得到很好的描述。为了填补这一知识空白，我们对感染 EBOV-Makona 的食蟹猴组织中的纵向转录变化进行了追踪。感染后，肝脏和肾上腺都表现出与代谢、凝血、激素合成和血管生成相关的基因的显著和早期下调；上调的基因与炎症有关。对淋巴组织的分析表明，先天免疫和炎症相关的基因早期上调，与细胞周期和适应性免疫相关的基因下调。此外，流式细胞术证实了淋巴组织中固有免疫反应的短暂激活和体液免疫反应的下调。综上所述，这些数据表明肝脏、肾上腺和淋巴器官是 EBOV 感染的重要部位，这些重要器官的功能失调导致了埃博拉病毒病的发展。埃博拉病毒（EBOV）仍然是一种高优先级的病原体，因为它继续导致高病死率的疫情爆发。尽管已经确定 EBOV 会导致严重的器官损伤，但我们对肝脏、肾上腺和淋巴组织中的组织损伤的理解仍然有限。我们通过对感染 EBOV 的食蟹猴组织进行纵向基因表达研究来开始填补这一知识空白。我们报告了这些组织中强大而早期的基因表达变化，表明它们是 EBOV 感染的主要部位。此外，参与代谢、凝血和适应性免疫的基因下调，而与炎症相关的基因上调。这些结果表明存在显著的组织损伤，与出血热和淋巴细胞减少的发展一致。我们的研究提供了对 EBOV-宿主相互作用的新见解，并阐明了肝脏、肾上腺和淋巴组织内的宿主反应如何导致 EBOV 发病机制。
