Impact of envelope proteins on poxviral pathogenesis

 描述（由申请方提供）：痘病毒是双链DNA病毒，其蛋白质核心被脂质包膜包围。包埋在脂质包膜中的是四种保守的病毒蛋白，它们被认为介导病毒结合。虽然这些蛋白质的功能已经在体外研究，但它们对痘病毒的嗜性和体内发病机制的影响仍然未知。我们现在提出的数据表明，去除这些包膜蛋白之一，假定的软骨素结合蛋白M083L，从兔痘病毒粘液瘤显着减弱病毒的发病机制，在进化相关的宿主物种通过限制系统性病毒传播。重要的是，M083的缺失严重限制了粘液瘤病毒对活化T细胞的嗜性，提供了该蛋白影响病毒传播的直接机制。然而，其余三种痘病毒包膜蛋白的作用仍然未知。因此，我们提出了目前的建议，旨在通过以下方式确定每种保守的痘病毒包膜蛋白如何影响病毒嗜性和疾病发病机制：从MYXV的基因组中去除每个病毒包膜蛋白，（具体目标1），表征这些包膜蛋白的去除如何影响体外病毒复制（具体目标2），以及鉴定去除每种病毒包膜蛋白如何影响体内病毒嗜性和发病机制（具体目标3）。我们预计，拟议的研究将揭示如何每个单独的痘病毒包膜蛋白影响病毒的发病机制和嗜性在体内。这些研究不仅将促进我们对基本痘病毒生物学的理解，而且还将通过允许痘病毒疫苗接种策略的合理设计和通过增加我们对如何改变体内病毒嗜性以增加病毒传播和递送到残留疾病部位的理解来改善基于痘病毒的溶瘤剂来显著影响公共卫生。

 DESCRIPTION (provided by applicant): Poxviruses are double-stranded DNA viruses whose protein core is surrounded by a lipid envelope. Embedded into the lipid envelope are four conserved viral proteins which are thought to mediate viral binding. While the function of these proteins has been studied in vitro, their impact on poxviral tropism and pathogenesis in vivo remains unknown. We now present data demonstrating that removal of one of these envelope proteins, the putative chondroitin binding protein M083L, from the leporipoxvirus myxoma significantly attenuates viral pathogenesis in an evolutionarily relevant host species by limiting systemic viral dissemination. Critically, loss of M083 severely restricts myxoma virus tropism for activated T cells providing a direct mechanism through which this protein impacts viral dissemination. The roles of the remaining three poxviral envelope proteins, however, remains unknown. We therefore put forth the current proposal designed to identify how each of the conserved poxviral envelope proteins impacts viral tropism and disease pathogenesis by: removing each viral envelope protein from the genome of MYXV (Specific Aim 1), characterizing how removal of these envelope proteins impacts viral replication in vitro (Specific Aim 2), and identifying how removal of each viral envelope protein impacts viral tropism and pathogenesis in vivo (Specific Aim 3). We anticipate that the proposed studies will uncover how each individual poxviral envelope protein impacts viral pathogenesis and tropism in vivo. These studies will not only advance our understanding of basic poxviral biology but will also significantly impact public health both by allowing for rationale design of poxviral vaccination strategies and improving poxvirus-based oncolytics by increasing our understanding of how to alter viral tropism in vivo to increase viral dissemination and delivery to sites of residual disease.