Division of Virology, Paul Ehrlich Institute, Langen, Germany.
J Virol. 2024 Jul 23;98(7):e0058024. doi: 10.1128/jvi.00580-24. Epub 2024 Jun 10.
Hepatitis E virus (HEV) poses a global threat, which currently remains understudied in terms of host interactions. Epidermal growth factor receptor (EGFR) plays multifaceted roles in viral pathogenesis, impacting host-cell entry, viral replication, and host-defense modulation. On the one hand, EGFR signaling emerged as a major driver in innate immunity; on the other hand, a crosstalk between HEV and EGFR requires deeper analysis. We therefore aimed to dissect the receptor's involvement in the HEV life cycle. In persistently HEV-infected cells, the EGFR amount is decreased alongside with enhanced receptor internalization. As compared with the control ligand-induced EGFR, activation revealed an early receptor internalization and degradation in HEV-replicating cells, resulting in a notable EGFR signaling delay. Interestingly, inhibition or silencing of EGFR increased viral replication, extracellular and intracellular viral transcripts, and released infectious particles. The pro-viral impact of EGFR inhibition was attributed to (i) impaired expression of interferon-stimulated genes, (ii) activation of the autophagosomal system, (iii) virus-induced inhibition of lysosomal acidification, and (iv) a decrease of the cellular cholesterol level.
This study identifies epidermal growth factor receptor (EGFR) as a novel host factor affecting hepatitis E virus (HEV): EGFR downregulation promotes viral replication, release, and evasion from the innate immune response. The discovery that EGFR inhibition favors viral spread is particularly concerning for HEV patients undergoing EGFR inhibitor treatment.
戊型肝炎病毒 (HEV) 构成全球性威胁，但目前其宿主相互作用的研究仍不够充分。表皮生长因子受体 (EGFR) 在病毒发病机制中具有多方面的作用，影响宿主细胞进入、病毒复制和宿主防御调节。一方面，EGFR 信号转导已成为先天免疫的主要驱动因素；另一方面，HEV 与 EGFR 之间的串扰需要更深入的分析。因此，我们旨在剖析受体在 HEV 生命周期中的作用。在持续感染 HEV 的细胞中，EGFR 的数量减少，同时受体内化增强。与对照配体诱导的 EGFR 相比，HEV 复制细胞中的激活显示出早期受体内化和降解，导致明显的 EGFR 信号延迟。有趣的是，EGFR 的抑制或沉默会增加病毒复制、细胞外和细胞内病毒转录本以及释放的感染性颗粒。EGFR 抑制的促病毒作用归因于 (i) 干扰素刺激基因表达的受损，(ii) 自噬体系统的激活，(iii) 病毒诱导的溶酶体酸化抑制，以及 (iv) 细胞胆固醇水平降低。
本研究确定表皮生长因子受体 (EGFR) 是影响戊型肝炎病毒 (HEV) 的新型宿主因素：EGFR 的下调促进了病毒的复制、释放和逃避先天免疫反应。发现 EGFR 抑制有利于病毒传播，这对正在接受 EGFR 抑制剂治疗的 HEV 患者尤其令人担忧。
