Pathogenesis of Jeilongvirus

项目总结 J副粘病毒(JPV)于20世纪70年代初在澳大利亚从啮齿动物中首次分离到。它的基因组结构是 2005年确定的。JPV基因组有8个基因，其顺序为3‘-N-P/V/C-M-F-SH-TM-G-L-5’。JPV 编码一种TM(跨膜)蛋白，它与任何已知的蛋白质没有同源性，也不存在于任何 其他机密副粘病毒。2006年从人肾系膜组织中分离到北龙病毒。 细胞(HMCS)作为来自大鼠细胞系的污染物。北PV与JPV具有相同的基因组结构。研究 提示北汽是一种啮齿动物病毒。由于它们独特的基因组结构，一个新的属，吉隆病毒， 建议将JPV和BEV归入副粘病毒家族。泰兰病毒(TlmPV)，分离自 2011年香港一只锡金大鼠的肾脏，与JPV和北京PV具有相同的基因组结构， 这表明它是吉隆病毒属的一个成员。2014年，吉隆病毒属的一个可能成员是 从英国灰松鼠肾脏细胞的原代培养中鉴定出来。此外，该基因的RNA序列 在非洲、欧洲和中国(个人)的啮齿动物和蝙蝠中发现了JPV样病毒 自2012年以来)，表明吉隆病毒分布广泛，感染多种哺乳动物。 目前，人们对这类新出现的病毒知之甚少。针对JPV的抗体有 在啮齿动物、猪和人类中检测到JPV，这表明JPV具有广泛的宿主范围和人畜共患病 潜力。在蝙蝠身上发现了吉隆病毒，这一事实说明了它们在人畜共患病方面的潜力，因为蝙蝠 被认为是许多新出现的人畜共患病病毒的天然宿主，如SARS-CoV、Hendra和 尼帕病毒和埃博拉病毒。在哺乳动物的每一种副粘病毒中，都有重要的人类 病原体。因此，有理由预计吉隆病毒属中的一种病毒是致病的 人类。研究JPV很重要，原因如下：(1)万一一种致病的人类吉隆病毒 (2)JPV可作为研究猪细小病毒的模型。 副粘病毒的小分子疏水蛋白的功能；以及(3)JPV的TM的独特之处在于它是 副粘病毒家族中唯一在细胞间融合中起关键作用的病毒蛋白，但它不是 对于病毒到细胞的融合是必不可少的。 我们之所以选择JPV作为吉隆病毒的原型，是因为我们已经鉴定出一种JPV毒株，即 在实验室小鼠中致病。在这份提案中，我们计划对JPV进行全面分析，重点是 浅谈SH和TM的功能及其在动物发病机制中的作用为了实现这些目标， 我们已经建立了体内发病机制研究的动物模型和反向遗传学系统 操纵JPV的RNA基因组。此外，我们还产生了多克隆和单克隆抗体 所有的JPV蛋白。在这项建议中，我们将重点关注以下具体目标：(1)阐明 SH及其作用机制；(2)了解TM的体内外功能。 JPV代表了一类尚未被研究的新病毒。我们提议的工作将引导我们 在其中一种是人类致病的情况下开发潜在的对策，并提供新的 有关病毒蛋白功能和进入过程的知识。

PROJECT SUMMARY J paramyxovirus (JPV) was first isolated from rodents in the early 1970s in Australia. Its genome structure was determined In 2005. The JPV genome has eight genes in the order of 3'-N-P/V/C-M-F-SH-TM-G-L-5'. JPV encodes a TM (transmembrane) protein that has no homology to any known proteins and does not exist in any other classified paramyxoviruses. In 2006, Beilong virus (BeiPV) was isolated from human kidney mesangial cells (HMCs) as a contaminant from a rat cell line. BeiPV has the same genome structure as JPV. Studies indicate that BeiPV is a rodent virus. Because of their unique genome structure, a new genus, Jeilongvirus, was proposed to classify JPV and BeiPV within the paramyxovirus family. Tailam virus (TlmPV), isolated from the kidney of a Sikkim rat in Hong Kong in 2011, has an identical genome structure as JPV and BeiPV, indicating that it is a member of Jeilongvirus genus. In 2014, a likely member of Jeilongvirus genus was identified from the primary culture of grey squirrel kidney cells from the UK. In addition, RNA sequences of JPV-like viruses have been identified in rodents and bats in Africa, Europe, and China (personal communication) since 2012, indicating that Jeilongvirus is widely distributed and infects a variety of mammals. At present, very little is known about this new and emerging class of viruses. Antibodies against JPV have been detected in rodents, pigs, and humans, suggesting that JPV has a broad host range and zoonotic potential. The fact that Jeilongviruses have been identified in bats illustrates their zoonotic potential, since bats are thought to be the natural reservoirs for many emerging zoonotic viruses such as SARS-CoV, Hendra and Nipah viruses and Ebola virus. In every genus of mammalian paramyxoviruses, there are important human pathogens. Thus, it is reasonable to expect that one of the viruses in the Jeilongvirus genus is pathogenic in humans. It is important to study JPV for following reasons: (1) in case a pathogenic human Jeilongvirus emerges, we will have knowledge about this class of viruses; (2) JPV can be used as a model for the study of the functions of the small hydrophobic (SH) protein of paramyxoviruses; and (3) TM of JPV is unique in that it is the only viral protein in the paramyxovirus family that plays a critical role in cell-to-cell fusion, but it is not essential for virus-to-cell fusion. We have chosen JPV as a prototype of Jeilongvirus, because we have identified a strain of JPV that is pathogenic in laboratory mice. In this proposal, we plan to carry out a comprehensive analysis of JPV, focusing on understanding the functions of SH and TM and their roles in pathogenesis in animals. Towards these goals, we have established an animal model for in vivo pathogenesis studies and a reverse genetics system for manipulating the RNA genome of JPV. In addition, we have generated polyclonal and monoclonal antibodies for all JPV proteins. In this proposal, we will focus on following specific aims: (1) Elucidating the functions of SH and the mechanisms of its functions and (2) Understanding the functions of TM in vitro and in vivo. JPV represents a new class of viruses that have not been studied. Our proposed work will guide us in developing potential countermeasures in case one of them is pathogenic in humans and provide new knowledge regarding viral protein functions and entry processes.