Transcriptional Analysis of Infection With Early or Late Isolates From the 2013-2016 West Africa Ebola Virus Epidemic Does Not Suggest Attenuated Pathogenicity as a Result of Genetic Variation.
Transcriptional Analysis of Infection With Early or Late Isolates From the 2013-2016 West Africa Ebola Virus Epidemic Does Not Suggest Attenuated Pathogenicity as a Result of Genetic Variation.
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DOI：
10.3389/fmicb.2021.714817
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发表时间：
2021
影响因子：
5.2
通讯作者：
Messaoudi I
中科院分区：
文献类型：
--
作者：
Maroney KJ;Pinski AN;Marzi A;Messaoudi I
2013-2016年西非埃博拉病毒（EBOV）流行由EBOV-Makona分离株引起，是迄今为止最大和最长的记录。它导致28，000多人感染，11，000人死亡。在这次流行的早期，病毒糖蛋白（A82 V）、核蛋白（R111 C）和聚合酶L（D 759 G）出现了几个突变并稳定下来。对这些新的EBOV-Makona分离株的体外研究表明，适应性和病毒复制能力增强。然而，在小鼠和恒河猴中的体内研究没有提供任何增强病毒适应性或脱落的证据。携带这些突变的晚期分离株或缺乏（早期）这些突变的早期分离株感染导致非人灵长类动物（NHP）的一致致死性疾病，尽管晚期分离株的动力学略有延迟。最近关于EBOV可能从流行病幸存者的持续感染中重新出现的报道突出了了解遗传变异对EBOV发病机制的影响的紧迫性。然而，宿主反应的潜在分子差异仍然未知。为了解决这一知识差距，我们使用双变量、纵向、回归和判别转录组学分析对EBOV-Mayinga和EBOV-Makona分离株致死感染的宿主反应进行了首次比较分析。我们的分析显示了一个保守的核心差异表达基因（DEG）参与抗病毒防御，免疫细胞激活，炎症过程中响应EBOV-Makona和EBOV-Mayinga感染。此外，EBOV-Makona和EBOV-Mayinga感染可以基于一小部分基因的表达模式来区分。对流行期间后期出现的EBOV-Makona分离株的转录应答，特别是来自马里和利比里亚的那些，缺乏感染EBOV-Mayinga和早期EBOV-Makona分离株C 07后观察到的严重淋巴细胞减少和过度炎症的特征。总的来说，这些发现为EBOV-Makona与EBOV-Mayinga相比观察到的较低病死率（CFR）的机制提供了新的见解。
The 2013–2016 West Africa Ebola virus (EBOV) epidemic caused by the EBOV-Makona isolate is the largest and longest recorded to date. It incurred over 28,000 infections and ∼11,000 deaths. Early in this epidemic, several mutations in viral glycoprotein (A82V), nucleoprotein (R111C), and polymerase L (D759G) emerged and stabilized. In vitro studies of these new EBOV-Makona isolates showed enhanced fitness and viral replication capacity. However, in vivo studies in mice and rhesus macaques did not provide any evidence of enhanced viral fitness or shedding. Infection with late isolates carrying or early isolates lacking (early) these mutations resulted in uniformly lethal disease in nonhuman primates (NHPs), albeit with slightly delayed kinetics with late isolates. The recent report of a possible reemergence of EBOV from a persistent infection in a survivor of the epidemic highlights the urgency for understanding the impact of genetic variation on EBOV pathogenesis. However, potential molecular differences in host responses remain unknown. To address this gap in knowledge, we conducted the first comparative analysis of the host responses to lethal infection with EBOV-Mayinga and EBOV-Makona isolates using bivariate, longitudinal, regression, and discrimination transcriptomic analyses. Our analysis shows a conserved core of differentially expressed genes (DEGs) involved in antiviral defense, immune cell activation, and inflammatory processes in response to EBOV-Makona and EBOV-Mayinga infections. Additionally, EBOV-Makona and EBOV-Mayinga infections could be discriminated based on the expression pattern of a small subset of genes. Transcriptional responses to EBOV-Makona isolates that emerged later during the epidemic, specifically those from Mali and Liberia, lacked signatures of profound lymphopenia and excessive inflammation seen following infection with EBOV-Mayinga and early EBOV-Makona isolate C07. Overall, these findings provide novel insight into the mechanisms underlying the lower case fatality rate (CFR) observed with EBOV-Makona compared to EBOV-Mayinga.
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影响因子：
30.3
作者：
Eisfeld AJ;Halfmann PJ;Wendler JP;Kyle JE;Burnum-Johnson KE;Peralta Z;Maemura T;Walters KB;Watanabe T;Fukuyama S;Yamashita M;Jacobs JM;Kim YM;Casey CP;Stratton KG;Webb-Robertson BM;Gritsenko MA;Monroe ME;Weitz KK;Shukla AK;Tian M;Neumann G;Reed JL;van Bakel H;Metz TO;Smith RD;Waters KM;N'jai A;Sahr F;Kawaoka Y
通讯作者：
Kawaoka Y
影响因子：
19
作者：
Bell, A.;Lewandowski, K.;Zambon, M.
通讯作者：
Zambon, M.
影响因子：
5.4
作者：
Fausther-Bovendo, H.;Qiu, X.;Kobinger, G.
通讯作者：
Kobinger, G.
影响因子：
3
作者：
H Backman TW;Girke T
通讯作者：
Girke T
影响因子：
168.9
作者：
Gaudinski, Martin R.;Coates, Emily E.;Ledgerwood, Julie E.
通讯作者：
Ledgerwood, Julie E.