An increase in glycoprotein concentration on extracellular virions dramatically alters vaccinia virus infectivity and pathogenesis without impacting immunogenicity.
An increase in glycoprotein concentration on extracellular virions dramatically alters vaccinia virus infectivity and pathogenesis without impacting immunogenicity.
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细胞外病毒粒子上糖蛋白浓度的增加会显着改变痘苗病毒的感染性和发病机制，而不影响免疫原性。
DOI：
10.1371/journal.ppat.1010177
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发表时间：
2021-12
期刊：
影响因子：
6.7
通讯作者：
Ward BM
中科院分区：
文献类型：
--
作者：
Monticelli SR;Bryk P;Brewer MG;Aguilar HC;Norbury CC;Ward BM
正痘病毒的细胞外病毒粒子（EV）形式是细胞间传播和发病所必需的，并且是保护性免疫反应中中和抗体的目标。肠病毒具有双包膜，其中包含几种独特的蛋白质，这些蛋白质参与其细胞内包膜和/或随后的传染性。其中之一，F13，参与了肠病毒的形成和传染性。在这里，我们报告用传染性软疣病毒同源物MC021L替代牛痘病毒F13L，导致EV颗粒的产生，EV糖蛋白水平显著增加，这与小斑块表型相关。利用一种新的荧光激活病毒粒子分选方法，根据糖蛋白含量分离出EV种群，我们确定含有较高或较低糖蛋白水平的EV传染性较低，这表明EV具有最大感染性所需的最佳外包膜糖蛋白浓度。在动物感染的皮肤模型中，这种最佳糖蛋白浓度是致死性和诱导病理所必需的，但不是诱导保护性免疫反应所必需的。因此，我们的研究结果表明，在糖蛋白掺入、传染性和发病机制之间存在一个敏感的平衡，并且操纵EV糖蛋白水平可以产生疫苗载体，在这种载体中，病理副作用被减弱，而保护性免疫的诱导却没有明显减弱。病毒糖蛋白是宿主细胞趋向性、免疫和发病机制的关键决定因素。牛痘病毒被用于历史上最成功的免疫规划，痘病毒继续被用作疫苗载体。在这里，我们报道了牛痘病毒细胞外病毒粒子（EV）蛋白F13在控制糖蛋白结合中起着重要的作用，并且糖蛋白浓度与随后的感染性之间存在直接关系，这是以前未被认识到的。关键是，在体内感染模型中，操纵EV糖蛋白浓度改变了发病机制和致死率，但没有显著改变诱导的免疫反应。这些结果对通过改变糖蛋白含量来设计更安全、更有效的痘病毒疫苗载体具有重要意义。
The extracellular virion (EV) form of Orthopoxviruses is required for cell-to-cell spread and pathogenesis, and is the target of neutralizing antibodies in the protective immune response. EV have a double envelope that contains several unique proteins that are involved in its intracellular envelopment and/or subsequent infectivity. One of these, F13, is involved in both EV formation and infectivity. Here, we report that replacement of vaccinia virus F13L with the molluscum contagiosum virus homolog, MC021L, results in the production of EV particles with significantly increased levels of EV glycoproteins, which correlate with a small plaque phenotype. Using a novel fluorescence-activated virion sorting assay to isolate EV populations based on glycoprotein content we determine that EV containing either higher or lower levels of glycoproteins are less infectious, suggesting that there is an optimal concentration of glycoproteins in the outer envelope that is required for maximal infectivity of EV. This optimal glycoprotein concentration was required for lethality and induction of pathology in a cutaneous model of animal infection, but was not required for induction of a protective immune response. Therefore, our results demonstrate that there is a sensitive balance between glycoprotein incorporation, infectivity, and pathogenesis, and that manipulation of EV glycoprotein levels can produce vaccine vectors in which pathologic side effects are attenuated without a marked diminution in induction of protective immunity. Viral glycoproteins are critical determinants of host cell tropism, immunity, and pathogenesis. Vaccinia virus was used for the most successful immunization program in history, and poxviruses continue to be used as vaccine vectors. Here, we report that vaccinia virus extracellular virion (EV) protein F13 plays an important, previously unappreciated, role in controlling glycoprotein incorporation, and that there is a direct relationship between glycoprotein concentrations and subsequent infectivity. Crucially, manipulation of the EV glycoprotein concentrations altered pathogenesis and lethality in an in vivo infection model, but did not markedly alter the induced immune response. These results have important implications that inform the design of safer and more efficacious poxvirus-based vaccine vectors by altering glycoprotein content.
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