Division of Viral Hepatitis, National Center for HIV/AIDS, Viral Hepatitis, STD and TB Prevention, The Centers for Disease Control and Prevention, Atlanta, Georgia, United States of America.
Office of Advanced Molecular Detection, National Center for Emerging and Zoonotic Infectious Diseases, The Centers for Disease Control and Prevention, Atlanta, Georgia, United States of America.
PLoS One. 2020 Sep 2;15(9):e0237618. doi: 10.1371/journal.pone.0237618. eCollection 2020.
Hepatitis E virus (HEV) genotype 1 (gt1) and gt3 infections have distinct epidemiologic characteristics and genotype-specific molecular mechanisms of pathogenesis are not well characterized. Previously, we showed differences in immune response-related gene expression profiles of HEV gt1 and gt3 infections using qPCR. We hypothesize that HEV gt1 and gt3 infections induce transcriptome modifications contributing to disease pathogenesis. RNAseq analysis was performed using liver biopsy samples of naïve (baseline), HEV gt1, or gt3-infected rhesus macaques, and nine anti-HEV positive rhesus macaques re-inoculated with HEV gt1. All 10 primary HEV gt1/gt3 infected animals exhibited the typical course of acute viral hepatitis and cleared the infection between 27 to 67 days after inoculation. Viremic stages of HEV infection were defined as early, peak, and decline based on HEV RNA titers in daily stool specimens. During early, peak, and decline phases of infection, HEV gt1 induced 415, 417, and 1769 differentially expressed genes, respectively, and 310, 678, and 388 genes were differentially expressed by HEV gt3, respectively (fold change ≥ 2.0, p-value ≤ 0.05). In the HEV gt1 infection, genes related to metabolic pathways were differentially expressed during the three phases of infection. In contrast, oxidative reduction (early phase), immune responses (peak phase), and T cell cytokine production (decline phase) were found to be regulated during HEV gt3 infection. In addition, FoxO and MAPK signaling pathways were differentially regulated in re-infected and protected animals against HEV gt1 reinfection, respectively. Significant differences of hepatic gene regulation exist between HEV gt1 and gt3 infections. These findings reveal a new link between molecular pathogenesis and epidemiological characteristics seen in HEV gt1 and gt3 infections.
戊型肝炎病毒（HEV）基因型 1（gt1）和 gt3 感染具有不同的流行病学特征，且基因型特异性发病机制的分子机制尚未得到很好的描述。此前，我们使用 qPCR 显示了 HEV gt1 和 gt3 感染的免疫反应相关基因表达谱的差异。我们假设 HEV gt1 和 gt3 感染诱导导致发病机制的转录组修饰。使用未经感染（基线）、HEV gt1 或 gt3 感染的恒河猴肝活检样本进行 RNAseq 分析，并用 9 只抗 HEV 阳性的恒河猴再感染 HEV gt1。所有 10 只原发性 HEV gt1/gt3 感染动物均表现出典型的急性病毒性肝炎病程，并在接种后 27 至 67 天清除感染。根据每日粪便标本中的 HEV RNA 滴度，将 HEV 感染的病毒血症阶段定义为早期、高峰和下降期。在感染的早期、高峰和下降期，HEV gt1 分别诱导了 415、417 和 1769 个差异表达基因，而 HEV gt3 分别诱导了 310、678 和 388 个差异表达基因（倍数变化≥2.0，p 值≤0.05）。在 HEV gt1 感染中，在感染的三个阶段中，与代谢途径相关的基因差异表达。相比之下，在 HEV gt3 感染中，发现氧化还原（早期阶段）、免疫反应（高峰阶段）和 T 细胞细胞因子产生（下降阶段）受到调节。此外，FoxO 和 MAPK 信号通路在再次感染和保护动物中分别受到不同调节，以抵抗 HEV gt1 再感染。HEV gt1 和 gt3 感染之间存在显著的肝基因调控差异。这些发现揭示了 HEV gt1 和 gt3 感染中分子发病机制和流行病学特征之间的新联系。
