Honey bees (Apis mellifera L.) suffer from many brood pathogens, including viruses. Despite considerable research, the molecular responses and dynamics of honey bee pupae to viral pathogens remain poorly understood. Israeli Acute Paralysis Virus (IAPV) is emerging as a model virus since its association with severe colony losses. Using worker pupae, we studied the transcriptomic and methylomic consequences of IAPV infection over three distinct time points after inoculation. Contrasts of gene expression and 5 mC DNA methylation profiles between IAPV-infected and control individuals at these time points – corresponding to the pre-replicative (5 h), replicative (20 h), and terminal (48 h) phase of infection – indicate that profound immune responses and distinct manipulation of host molecular processes accompany the lethal progression of this virus. We identify the temporal dynamics of the transcriptomic response to with more genes differentially expressed in the replicative and terminal phases than in the pre-replicative phase. However, the number of differentially methylated regions decreased dramatically from the pre-replicative to the replicative and terminal phase. Several cellular pathways experienced hyper- and hypo-methylation in the pre-replicative phase and later dramatically increased in gene expression at the terminal phase, including the MAPK, Jak-STAT, Hippo, mTOR, TGF-beta signaling pathways, ubiquitin mediated proteolysis, and spliceosome. These affected biological functions suggest that adaptive host responses to combat the virus are mixed with viral manipulations of the host to increase its own reproduction, all of which are involved in anti-viral immune response, cell growth, and proliferation. Comparative genomic analyses with other studies of viral infections of honey bees and fruit flies indicated that similar immune pathways are shared. Our results further suggest that dynamic DNA methylation responds to viral infections quickly, regulating subsequent gene activities. Our study provides new insights of molecular mechanisms involved in epigenetic that can serve as foundation for the long-term goal to develop anti-viral strategies for honey bees, the most important commercial pollinator.

蜜蜂（意大利蜜蜂L.) 患有许多巢病原体，包括病毒。尽管进行了大量研究，但蜜蜂蛹对病毒病原体的分子反应和动力学仍然知之甚少。以色列急性麻痹病毒（IAPV）由于与严重的菌落损失相关而成为一种模型病毒。使用工蜂蛹，我们研究了接种后三个不同时间点 IAPV 感染的转录组和甲基组后果。IAPV 感染者和对照个体在这些时间点（对应于感染的复制前（5 小时）、复制（20 小时）和终末（48 小时）阶段）之间的基因表达和 5 mC DNA 甲基化谱的对比表明深刻的免疫反应和对宿主分子过程的独特操纵伴随着这种病毒的致命进展。我们确定了转录组反应的时间动态，在复制期和终末期比复制前期差异表达的基因更多。然而，从复制前到复制和终末期，差异甲基化区域的数量急剧减少。一些细胞通路在复制前阶段经历了高甲基化和低甲基化，随后在末期基因表达显着增加，包括 MAPK、Jak-STAT、Hippo、mTOR、TGF-β 信号通路、泛素介导的蛋白水解、和剪接体。这些受影响的生物功能表明，对抗病毒的适应性宿主反应与宿主的病毒操作混合在一起，以增加其自身的繁殖，所有这些都参与抗病毒免疫反应、细胞生长和增殖。与其他蜜蜂和果蝇病毒感染研究的比较基因组分析表明，它们具有相似的免疫途径。我们的结果进一步表明，动态 DNA 甲基化对病毒感染做出快速反应，调节随后的基因活动。我们的研究提供了有关表观遗传的分子机制的新见解，可以作为为蜜蜂（最重要的商业授粉媒介）开发抗病毒策略的长期目标的基础。