Tafesh-Edwards Ghada, Kalukin Ananda, Eleftherianos Ioannis
Infection and Innate Immunity Laboratory, Department of Biological Sciences, The George Washington University, Washington, DC, United States.
Front Immunol. 2022 Jun 30;13:903860. doi: 10.3389/fimmu.2022.903860. eCollection 2022.
Zika is a member of the virus family that poses some of the most significant global health risks, causing neurologic complications that range from sensory neuropathy and seizures to congenital Zika syndrome (microcephaly) in infants born to mothers infected during pregnancy. The recent outbreak of Zika virus (ZIKV) and its serious health threats calls for the characterization and understanding of Zika pathogenesis, as well as host antiviral immune functions. Although ZIKV has been associated with activating the RNA interference (RNAi) immune pathway and altering host metabolism, in-depth studies are still required to uncover the specifics of the complex host-virus interactions and provide additional insights into the molecular components that determine the outcome of this disease. Previous research establishes the fruit fly as a reliable model for studying viral pathogens, as it shares significant similarities with that of vertebrate animal systems. Here, we have developed an model to investigate ZIKV-mediated perturbed metabolism in correlation to the RNAi central mediator Dicer-2. We report that ZIKV infection reprograms glucose and glycogen metabolism in mutants to maintain efficient replication and successful propagation. Flies that exhibit these metabolic effects also show reduced food intake, which highlights the complicated neurological defects associated with ZIKV. We show that ZIKV infection significantly reduces insulin gene expression in mutants, suggesting an insulin antiviral role against ZIKV and a direct connection to RNAi immunity. Moreover, we find that the insulin receptor substrate c is crucial to the survival of ZIKV-infected flies. These observations are remarkably more severe in adult female flies compared to males, indicating possible sex differences in the rates of infection and susceptibility to the development of disease. Such findings not only demonstrate that metabolic alterations can be potentially exploited for developing immune therapeutic strategies but also that preventive measures for disease development may require sex-specific approaches. Therefore, further studies are urgently needed to explore the molecular factors that could be considered as targets to inhibit ZIKV manipulation of host cell metabolism in females and males.
寨卡病毒是病毒家族的一员，构成了一些最重大的全球健康风险，会引发神经并发症，从感觉神经病变和癫痫发作到孕期感染的母亲所生婴儿的先天性寨卡综合征（小头畸形）。最近寨卡病毒（ZIKV）的爆发及其严重的健康威胁，要求对寨卡病毒的发病机制以及宿主抗病毒免疫功能进行表征和了解。尽管ZIKV与激活RNA干扰（RNAi）免疫途径和改变宿主代谢有关，但仍需要深入研究以揭示复杂的宿主 - 病毒相互作用的细节，并为决定该疾病结果的分子成分提供更多见解。先前的研究确立果蝇是研究病毒病原体的可靠模型，因为它与脊椎动物系统有显著相似之处。在这里，我们开发了一个模型来研究与RNAi核心介质Dicer-2相关的ZIKV介导的代谢紊乱。我们报告说，ZIKV感染会重新编程果蝇突变体中的葡萄糖和糖原代谢，以维持高效复制和成功传播。表现出这些代谢效应的果蝇也显示食物摄入量减少，这突出了与ZIKV相关的复杂神经缺陷。我们表明，ZIKV感染会显著降低果蝇突变体中的胰岛素基因表达，表明胰岛素对ZIKV具有抗病毒作用，并与RNAi免疫有直接联系。此外，我们发现胰岛素受体底物c对ZIKV感染的果蝇的存活至关重要。与雄性果蝇相比，这些观察结果在成年雌性果蝇中明显更严重，表明在感染率和疾病易感性方面可能存在性别差异。这些发现不仅表明代谢改变可潜在地用于开发免疫治疗策略，而且疾病发展的预防措施可能需要针对性别的方法。因此，迫切需要进一步研究以探索可被视为抑制ZIKV操纵雌性和雄性宿主细胞代谢的靶点的分子因素。
