Department of Microbiology and Immunology, Stritch School of Medicine, Loyola University Chicago, Maywood, Illinois 60153, United States.
Infectious Disease and Immunology Research Institute, Stritch School of Medicine, Loyola University Chicago, Maywood, Illinois 60153, United States.
ACS Infect Dis. 2020 Sep 11;6(9):2490-2501. doi: 10.1021/acsinfecdis.0c00402. Epub 2020 Aug 12.
Viruses require host cell metabolites to productively infect, and the mechanisms by which viruses usurp these molecules are diverse. One group of cellular metabolites important in virus infection is the polyamines, small positively charged molecules involved in cell cycle, translation, and nucleic acid metabolism, among other cellular functions. Polyamines support replication of diverse viruses, and they are important for processes such as transcription, translation, and viral protein enzymatic activity. Rift Valley fever virus (RVFV) is a negative and ambisense RNA virus that requires polyamines to produce infectious particles. In polyamine depleted conditions, noninfectious particles are produced that interfere with virus replication and stimulate immune signaling. Here, we find that RVFV relies on virion-associated polyamines to maintain infectivity and enhance viral entry. We show that RVFV replication is facilitated by a limited set of polyamines and that spermidine and closely related molecules associate with purified virions and transmit from cell to cell during infection. Virion-associated spermidine maintains virion infectivity, as virions devoid of polyamines rapidly lose infectivity and are temperature sensitive. Further, virions without polyamines bind to cells but exhibit a defect in entry, requiring more acidic conditions than virions containing spermidine. These data highlight a unique role for polyamines, and spermidine particularly, to maintain virus infectivity. Further, these studies are the first to identify polyamines associated with RVFV virions. Targeting polyamines represents a promising antiviral strategy, and this work highlights a new mechanism by which we can inhibit virus replication through FDA-approved polyamine depleting pharmaceuticals.
病毒需要宿主细胞代谢物才能有效地感染，而病毒篡夺这些分子的机制是多种多样的。一组在病毒感染中重要的细胞代谢物是多胺，这是一种带正电荷的小分子，参与细胞周期、翻译和核酸代谢等多种细胞功能。多胺支持多种病毒的复制，它们对转录、翻译和病毒蛋白酶活性等过程很重要。裂谷热病毒（RVFV）是一种负链和双义 RNA 病毒，需要多胺来产生感染性颗粒。在多胺耗尽的条件下，会产生非感染性颗粒，这些颗粒会干扰病毒复制并刺激免疫信号。在这里，我们发现 RVFV 依赖病毒粒子相关的多胺来维持感染力并增强病毒进入。我们表明，RVFV 的复制依赖于一组有限的多胺，并且精胺和密切相关的分子与纯化的病毒粒子结合，并在感染过程中从一个细胞传递到另一个细胞。病毒粒子相关的精胺维持病毒粒子的感染力，因为没有多胺的病毒粒子迅速失去感染力并且对温度敏感。此外，没有多胺的病毒粒子与细胞结合，但在进入时存在缺陷，需要比含有精胺的病毒粒子更低的酸性条件。这些数据突出了多胺的独特作用，特别是精胺，以维持病毒感染力。此外，这些研究首次鉴定了与 RVFV 病毒粒子相关的多胺。靶向多胺是一种很有前途的抗病毒策略，这项工作突出了一种新的机制，我们可以通过 FDA 批准的多胺耗竭药物来抑制病毒复制。
