Scholl Aaron, Gong Binsheng, Li Bingjie, Fatima Tahira, Tirrell Nikki, Karaiskos Spyros, Rios Maria, Xu Joshua, De Sandip
Tumor Vaccine and Biotechnology Branch, Division of Cellular Therapy 2, Office of Cellular Therapy and Human Tissue, Center for Biologics Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, MD 20993, United States.
Division of Bioinformatics and Biostatistics, Office of Research, National Center for Toxicological Research, U.S. Food and Drug Administration, Jefferson, AR 72079, United States.
NAR Mol Med. 2025 Apr;2(2). doi: 10.1093/narmme/ugaf015. Epub 2025 May 14.
Changes in global climate have contributed to increased tick and mosquito (vector) populations and subsequent vector-borne flavivirus infections in humans. This increase poses a threat to the safety of human-derived biologics such as cell and gene therapy. We conducted time-course transcriptomic and protein analyses to uncover host molecular factors driving the virulence of Zika virus (ZIKV) and Dengue virus (DENV) in relation to host defense mechanisms, as these viruses have caused recent flavivirus outbreaks. Compared to DENV, ZIKV exhibited stronger virulence and cytopathic effects. RNA-seq analysis revealed differential expression of various cellular factors, including RNA processing factors. Protein analysis showed ZIKV, unlike DENV, degrades nonsense-mediated RNA decay (NMD) factors in host cells, resulting in accumulated host intronic transcripts. We found that active nuclear transport is required for ZIKV replication. From our findings, we hypothesize that ZIKV drives early host cell cytopathy through targeted protein degradation. Studies are underway to develop novel strategies to detect flaviviruses in biologics based on transcriptomics and proteomics.
全球气候变化导致蜱虫和蚊子（病媒）数量增加，进而使人类感染病媒传播的黄病毒。这种增加对细胞和基因治疗等人类源生物制品的安全构成威胁。我们进行了时间进程转录组学和蛋白质分析，以揭示寨卡病毒（ZIKV）和登革病毒（DENV）的毒力与宿主防御机制相关的宿主分子因素，因为这些病毒最近引发了黄病毒疫情。与DENV相比，ZIKV表现出更强的毒力和细胞病变效应。RNA测序分析揭示了包括RNA加工因子在内的各种细胞因子的差异表达。蛋白质分析表明，与DENV不同，ZIKV会降解宿主细胞中的无义介导的RNA衰变（NMD）因子，导致宿主内含子转录本积累。我们发现ZIKV复制需要活跃的核运输。根据我们的发现，我们推测ZIKV通过靶向蛋白质降解驱动早期宿主细胞病变。目前正在开展研究，以开发基于转录组学和蛋白质组学检测生物制品中黄病毒的新策略。
