CD47 Homologues in Pathogenesis of Poxvirus Infection

描述(申请人提供)：本申请重点关注天花的发病机制，以回应RFA AI-02-002。天花是一个主要的生物恐怖主义威胁，因为它通过气雾剂途径传染；一旦确定感染，它就会在人与人之间迅速传播；它在未接种疫苗的个人中病死率很高；而且没有有效的治疗方法。由于对天花发病机制的研究在30多年前实际上已经结束，根据这种疾病的新威胁设计新的预防或治疗方法的知识库已经非常过时。所有测序的痘病毒基因组都含有一个开放阅读框架(ORF)，与普遍表达的脊椎动物质膜蛋白CD47同源。痘病毒表达许多与脊椎动物蛋白同源的蛋白质，包括细胞因子和细胞因子受体样基因、趋化因子和趋化因子受体样基因、补体控制蛋白和肿瘤坏死因子受体同源物。这些病毒蛋白被统称为免疫球蛋白，因为它们的目的是破坏正常的宿主免疫反应。此外，痘病毒表达CrmA和其他蛋白质，其主要目的是抑制受感染细胞的死亡。这两个家族的痘病毒蛋白对病毒的生存、复制和传播都很重要。CD47具有多种已知的功能，使其成为理想的病毒颠覆候选者，因为它在调节吞噬功能、吞噬细胞的激活和迁移、对颗粒抗原的免疫反应以及淋巴细胞的凋亡方面发挥作用。这一应用的假设是，在痘病毒基因组中与CD47同源的高度保守的开放阅读框架存在，以破坏这些CD47中的一个或多个功能，从而对病毒有利。了解这种痘病毒CD47同源物的功能可能会导致新的预防或治疗天花的方法。为了了解这种痘病毒ORF的功能，我们建议鉴定与CD47同源的天花和痘苗ORF的宿主细胞配体，并确定天花CD47同源物如何颠覆正常的CD47功能。对哺乳动物CD47的这种痘病毒同源物的进一步了解将有助于揭示天花的传播和发病机制，并将有助于开发预防和治疗这种疾病的新策略。

DESCRIPTION (provided by applicant): This application focuses on the pathogenesis of smallpox, in response to RFA AI-02-002. Smallpox is a major bioterrorism threat because it is infectious by the aerosol route; once infection is established it spreads rapidly from human to human; it has a high case fatality rate among unvaccinated individuals; and there is no effective treatment. Since research on the pathogenesis of smallpox effectively ended more than 30 years ago, the knowledge base for designing new methods for prevention or treatment in light of the new threat of this disease is woefully out of date. All sequenced poxvirus genomes contain an open reading frame (orf) homologous to the ubiquitously expressed vertebrate plasma membrane protein CD47. Poxviruses express a number of proteins homologous to vertebrate proteins, including cytokine- and cytokine receptor-like genes, chemokine- and chemokine receptor-like genes, complement control proteins, and TNF receptor homologues. These viral proteins have been collectively called immuno-evasins because of their purpose to undermine normal host immune responses. In addition poxviruses express crmA and other proteins whose main purpose is to inhibit the death of infected cells. Both families of poxvirus proteins are important for viral survival, replication, and transmission. CD47 has several known functions that make it an ideal candidate for viral subversion, since it has a role in regulation of phagocytosis, phagocyte activation and migration, immune response to particulate antigens, and apoptosis of lymphocytes. The hypothesis of this application is that the highly conserved open reading frame in poxvirus genomes homologous to CD47 exists to subvert one or more of these CD47 functions to the advantage of the virus. Understanding the functions of this poxvirus CD47 homologue could lead to new approaches to prevention or therapy of smallpox. To understand the functions of this poxvirus orf, we propose to identify host cell ligands for the Variola and Vaccinia orfs homologous to CD47 and determine how the Variola CD47 homologue subverts normal CD47 functions. This increased understanding of this poxvirus homologue of mammalian CD47 will shed light on transmission and pathogenesis of smallpox and will aid in the development of new strategies for prevention and treatment of this disease.