Pathophysiologic and transcriptomic analyses of viscerotropic yellow fever in a rhesus macaque model.
Pathophysiologic and transcriptomic analyses of viscerotropic yellow fever in a rhesus macaque model.
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DOI：
10.1371/journal.pntd.0003295
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发表时间：
2014
影响因子：
3.8
通讯作者：
Messaoudi I
中科院分区：
文献类型：
--
作者：
Engelmann F;Josset L;Girke T;Park B;Barron A;Dewane J;Hammarlund E;Lewis A;Axthelm MK;Slifka MK;Messaoudi I
黄热病病毒(YFV)是一种爆炸性复制的黄病毒，感染可导致以心血管休克和多器官衰竭为特征的病毒性出血性疾病。未接种疫苗的人口死亡率为20%至50%。由于暴发的零星性质和偏远地区，很少有研究检查YFV感染期间人类发生的病理生理变化。恒河猴对YFV感染高度敏感，为研究宿主与病原体的相互作用提供了一个可靠的动物模型。在这项研究中，我们描述了感染YFV强毒株DACKH1279(YFV-DACKH1279)的恒河猴的疾病进展以及免疫系统稳态、细胞因子产生和基因表达的变化。感染后，YFV-DACKH1279复制到高滴度，导致内脏疾病，∼死亡率为72%。这篇手稿中提供的数据首次表明，致命性YFV感染导致严重的淋巴细胞减少，这种情况先于肝酶的显著变化，尽管在肝脏、肾脏和淋巴组织中注意到组织损伤，但仅在肝脏中检测到病毒抗原。这些观察表明，额外的组织损伤可能是由于病毒复制的间接影响。事实上，几种细胞因子的循环水平在安乐死前不久达到了顶峰。我们的研究还首次描述了YFV-DACKH1279在感染后3天外周血单核细胞内基因表达的变化，在任何临床症状之前。这些数据表明，感染野生型YFV-DACKH1279或减毒活疫苗株YFV-17D分别导致了765个和46个差异表达基因(DEG)。YFV-17D感染后检测到的DEGS主要与先天免疫有关，而YFV-DACKH1279感染导致了与免疫反应、离子代谢和细胞凋亡相关的基因的失调。因此，WT-YFV感染与基因表达的显著变化有关，这些基因表达在临床症状出现之前就可以检测到，并可能影响疾病的进展和感染的结局。在非洲和南美洲，黄热病病毒每年导致∼200,000人感染和30,000人死亡。虽然这是一种重要的人类病原体，但黄热病严重程度的基础仍然知之甚少。恒河猴容易感染黄热病，并出现与人类相似的严重症状。在这项研究中，我们描述了这个模型中的疾病进展，并观察到在病毒诱导的肝脏病理的血清标记物出现之前，淋巴细胞的严重丢失。这一变化可能提供致命性黄热病的早期指标。此外，我们还发现，在出现任何可测量的疾病症状之前，白细胞中的基因表达发生了重大变化，这些基因特征可能为抗病毒治疗和更好的诊断提供未来的靶标。
Infection with yellow fever virus (YFV), an explosively replicating flavivirus, results in viral hemorrhagic disease characterized by cardiovascular shock and multi-organ failure. Unvaccinated populations experience 20 to 50% fatality. Few studies have examined the pathophysiological changes that occur in humans during YFV infection due to the sporadic nature and remote locations of outbreaks. Rhesus macaques are highly susceptible to YFV infection, providing a robust animal model to investigate host-pathogen interactions. In this study, we characterized disease progression as well as alterations in immune system homeostasis, cytokine production and gene expression in rhesus macaques infected with the virulent YFV strain DakH1279 (YFV-DakH1279). Following infection, YFV-DakH1279 replicated to high titers resulting in viscerotropic disease with ∼72% mortality. Data presented in this manuscript demonstrate for the first time that lethal YFV infection results in profound lymphopenia that precedes the hallmark changes in liver enzymes and that although tissue damage was noted in liver, kidneys, and lymphoid tissues, viral antigen was only detected in the liver. These observations suggest that additional tissue damage could be due to indirect effects of viral replication. Indeed, circulating levels of several cytokines peaked shortly before euthanasia. Our study also includes the first description of YFV-DakH1279-induced changes in gene expression within peripheral blood mononuclear cells 3 days post-infection prior to any clinical signs. These data show that infection with wild type YFV-DakH1279 or live-attenuated vaccine strain YFV-17D, resulted in 765 and 46 differentially expressed genes (DEGs), respectively. DEGs detected after YFV-17D infection were mostly associated with innate immunity, whereas YFV-DakH1279 infection resulted in dysregulation of genes associated with the development of immune response, ion metabolism, and apoptosis. Therefore, WT-YFV infection is associated with significant changes in gene expression that are detectable before the onset of clinical symptoms and may influence disease progression and outcome of infection. Yellow fever virus causes ∼200,000 infections and 30,000 deaths annually in Africa and South America. Although this is an important human pathogen, the basis of yellow fever disease severity remains poorly understood. Rhesus macaques are susceptible to yellow fever and develop similar symptoms as severe as those observed in humans. In this study, we characterized disease progression in this model and observed a profound loss of lymphocytes that preceded the appearance of serum markers of virus-induced liver pathology. This change might provide an early indicator of fatal yellow fever. In addition, we also identified significant changes in gene expression in white blood cells that occur before any measurable disease symptoms and these genetic signatures may provide future targets for antiviral therapeutics and better diagnostics.
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影响因子：
5.9
作者：
Falzarano, Darryl;Feldmann, Heinz
通讯作者：
Feldmann, Heinz
影响因子：
--
作者：
Fox, JP;Penna, HA
通讯作者：
Penna, HA
影响因子：
4.2
作者：
Ibs, KH;Rink, L
通讯作者：
Rink, L
影响因子：
168.9
作者：
Martin, M;Tsai, TF;Cetron, MS
通讯作者：
Cetron, MS
DOI：
10.1111/j.2517-6161.1995.tb02031.x
发表时间：
1995-01-01
影响因子：
5.8
作者：
BENJAMINI, Y;HOCHBERG, Y
通讯作者：
HOCHBERG, Y