LSUHSC COBRE:HERPESVIRUS US GLYCOPROTEINS IN SEVERE INFLAMMATORY DISEASE

LSUHSC COBRE：严重炎症性疾病中的疱疹病毒和糖蛋白

• 批准号: 7381982
• 负责人: PATRICK F SMITH
• 金额: $ 26.14万
• 依托单位: LOUISIANA STATE UNIV HSC SHREVEPORT
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-05-01 至 2007-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7381982
• 关键词: LSUHSC; COBRE; HERPESVIRUS; US; GLYCOPROTEINS

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Project 3: Role of Herpesvirus Us Glycoproteins in Severe Inflammatory Disease P.I. Project 3: Dr. Patrick M. Smith Abstract, Introduction, Specific Aims, and Progress. Many viruses infect humans, resulting in an almost endless range of outcomes of infection from subclinical disease to death. The delineation of mechanisms by which virus infection of humans results in serious outcomes including pneumonia, hepatitis, and encephalitis, is of particular importance because these clinical presentations are relatively common and are associated with significant morbidity and mortality. Mouse models have been used with success to reproduce many aspects of human disease from, to name only a few, lower respiratory disease by viral pathogens such as respiratory syncytial virus (RSV) and Influenzavirus A, to oncogenic transformation, persistent infection, and the establishment of latent infection by human herpesviruses. Intranasal infection of the mouse with equineherpes virus 1 (EHV-1) results in either a protective immune response within the lungs or a fatal immunopathological response, depending on the expression of only a very few viral gene products. This model allows us to assess how viral-host interactions can shift from protective to fatally immunopathologic as the result of only a very few virally-encoded glycoproteins. EHV-1 strain KyA is attenuated in the mouse (and equine) and causes no clinical signs of disease. In contrast, the RacL11 strain of EHV-1 induces a severe inflammatory infiltration in the lung, such that the majority of infected mice succumb to infection at days 3 to 6 post infection. To identify EHV-1 determinants responsible for these immunopathological responses, we focused on genes that have been deleted in the attenuated KyA strain but expressed in the pathogenic RacL11 strain. Compared to RacL11, KyA genes encoding glycoproteins I (gI) and E (gE) deleted and 1242 base pairs of the EUS4 gene that encodes gp2. By generating recombinant KyA with restored expression of differing combinations of these glycoproteins, we can assess the role that each plays in EHV-1 virulence. We recently published that restoration of the full-length form of gp2 to KyA (KyARgp2F) completely restored respiratory virulence to this otherwise fully attenuated EHV-1 strain indicating that gp2 is the sole determinant in EHV-1 respiratory disease in the mouse model. The restoration of gI and gE to KyA (KgIgE) resulted in neurologic disease and isolation of infectious KgIgE from the brain tissue, indicating that gI and gE allow entry of EHV into the central nervous system and spread to the brain. A complete listing of all recombinant EHV recently generated or in progress is listed below in Table 1. Recent work regarding each of these important EHV-encoded glycoproteins will be described below in context with each Specific Aim of the original proposal.

本子项目是利用由NIH/NCRR资助的中心赠款提供的资源的众多研究子项目之一。子项目和研究者（PI）可能已经从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。列出的机构是中心的，不一定是研究者的机构。项目3：疱疹病毒糖蛋白在严重炎性疾病中的作用P.I.项目3:Dr. Patrick M. Smith摘要，介绍，具体目的和进展。许多病毒感染人类，导致从亚临床疾病到死亡的几乎无穷无尽的感染结果。描述人类病毒感染导致肺炎、肝炎和脑炎等严重后果的机制尤其重要，因为这些临床表现相对常见，并与显著的发病率和死亡率相关。小鼠模型已被成功地用于复制人类疾病的许多方面，仅举几例，从呼吸道合胞病毒（RSV）和流感病毒a等病毒性病原体引起的下呼吸道疾病，到人类疱疹病毒的致癌转化、持续感染和潜伏感染的建立。马疱疹病毒1型（EHV-1）在小鼠鼻内感染导致肺内保护性免疫反应或致命的免疫病理反应，这仅取决于极少数病毒基因产物的表达。该模型使我们能够评估病毒-宿主相互作用如何从保护性转变为致命的免疫病理学，因为只有极少数病毒编码的糖蛋白。EHV-1株KyA在小鼠（和马）中减弱，不会引起临床疾病症状。相反，EHV-1的RacL11株诱导肺部严重的炎症浸润，因此大多数感染小鼠在感染后3至6天死亡。为了确定导致这些免疫病理反应的EHV-1决定因素，我们重点研究了在KyA减毒菌株中缺失但在致病性RacL11菌株中表达的基因。与RacL11相比，编码糖蛋白I （gI）和E （gE）的KyA基因缺失了编码gp2的EUS4基因的1242个碱基对。通过产生重组KyA，恢复这些糖蛋白的不同组合的表达，我们可以评估每种糖蛋白在EHV-1毒力中的作用。我们最近发表的研究表明，将gp2的全长形式恢复到KyA （KyARgp2F）完全恢复了对这种完全减弱的EHV-1菌株的呼吸道毒力，这表明gp2是小鼠模型中EHV-1呼吸道疾病的唯一决定因素。gI和gE恢复到KyA （KgIgE）导致神经系统疾病，并从脑组织中分离出感染性KgIgE，表明gI和gE允许EHV进入中枢神经系统并扩散到大脑。表1列出了最近产生或正在进行的所有重组超高压病毒的完整清单。关于这些重要的ehv编码糖蛋白的最新工作将在原始提案的每个特定目标的背景下进行描述。