Romero Alejandro, Figueras Antonio, Novoa Beatriz
Instituto de Investigaciones Marinas Spanish National Research Council (CSIC), Vigo, Spain.
Front Immunol. 2025 Apr 3;16:1576758. doi: 10.3389/fimmu.2025.1576758. eCollection 2025.
The spring viraemia of carp virus (SVCV) poses a significant threat to global aquaculture, yet effective antiviral drugs and vaccines remain unavailable. Understanding the interplay between host-pathogen interactions and SVCV replication is crucial for devising preventive strategies.
ZF4 cells were exposed to UV-inactivated SVCV or live SVCV at different multiplicities of infection, and the modulation of the unfolded protein response (UPR) was assayed by qPCR at different times. Moreover, ZF4 cells were treated with several UPR modulators to investigate their effect on viral replication. The UPR was also modulated in zebrafish larvae, and its impact on the survival against SVCV infection was evaluated.
This study reveals how SVCV exploits the host's UPR to facilitate its replication. SVCV targets the immunoglobulin heavy chain-binding protein (BiP) and the activating transcription factor 4 (ATF4) during early infection to enhance viral RNA synthesis and translation. At later stages, activation of the BiP, the PKR-like ER kinase (PERK), and the inositol-requiring enzyme 1 alpha (IRE1α) pathways supports the release of viral progeny and induces cellular processes, including immune responses and apoptotic cell death. Furthermore, the data demonstrate that modulating UPR pathways, particularly ATF6 and PERK, significantly affect viral replication, providing a novel avenue for antiviral drug development. Preliminary studies suggest the feasibility of chemically modulating the UPR to combat SVCV, though optimizing administration conditions to maximize efficacy while minimizing side effects warrants further investigation. These findings offer critical insights into the molecular mechanisms underlying SVCV pathogenesis and highlight promising targets for therapeutic intervention.
鲤春病毒血症病毒（SVCV）对全球水产养殖构成重大威胁，但仍缺乏有效的抗病毒药物和疫苗。了解宿主与病原体相互作用以及SVCV复制之间的相互关系对于制定预防策略至关重要。
将ZF4细胞以不同的感染复数暴露于紫外线灭活的SVCV或活的SVCV，并在不同时间通过qPCR检测未折叠蛋白反应（UPR）的调节情况。此外，用几种UPR调节剂处理ZF4细胞，以研究它们对病毒复制的影响。还在斑马鱼幼体中调节UPR，并评估其对抵抗SVCV感染存活的影响。
本研究揭示了SVCV如何利用宿主的UPR来促进其复制。SVCV在早期感染期间靶向免疫球蛋白重链结合蛋白（BiP）和激活转录因子4（ATF4），以增强病毒RNA合成和翻译。在后期，BiP、PKR样内质网激酶（PERK）和肌醇需求酶1α（IRE1α）途径的激活支持病毒子代的释放，并诱导包括免疫反应和凋亡性细胞死亡在内的细胞过程。此外，数据表明调节UPR途径，特别是ATF6和PERK，会显著影响病毒复制，为抗病毒药物开发提供了新途径。初步研究表明化学调节UPR以对抗SVCV具有可行性，尽管优化给药条件以在最小化副作用的同时最大化疗效仍有待进一步研究。这些发现为SVCV发病机制的分子机制提供了关键见解，并突出了有前景的治疗干预靶点。
