Defining the Role of the Neonatal Fc Receptor in a Novel Model of Echovirus II Infection

项目总结 肠道病毒是一个日益严重的公共卫生问题。肠道病毒，如脊髓灰质炎病毒、柯萨奇病毒 乙型(CVB)、埃科病毒和肠道病毒71型(EV71)通常会引起轻微症状。然而，新生儿和 儿童特别容易感染严重的肠道病毒感染，其特征是神经系统 脑炎、脑膜炎和瘫痪等并发症。此外，新生儿感染Echo病毒11型 (E11)导致肝功能衰竭，导致新生儿死亡。这些单链RNA病毒主要是 通过粪便-口腔途径传播，针对胃肠道(GI)。在GI中进行复制后 上皮，这些病毒传播到次要目标组织，如脑、胰腺和肝脏。许多 肠道病毒缺乏全面的小鼠模型，无法更好地了解 动物。因此，有必要开发更多的鼠标模型，以准确模拟 胃肠道上皮的相互作用以及建立某些肠道病毒的更完整的小鼠模型 研究继发感染部位的发病机制。目前，只有几种E11感染的小鼠模型存在 但它们不会模拟肝脏等次要部位的感染。在之前的研究中，我们已经确定了一种 泛爱可病毒受体，新生儿Fc受体(FcRN)。我们证明了人类转基因新生小鼠 表达FcRN(HFcRnTg)的人更容易感染Echo病毒11(E11)。我已经建立了一个 E11感染肝脏的成年小鼠模型，肝脏是人类感染的关键部位。我假设在那之后 E11从胃肠道传播，以FcRN依赖的方式感染肝脏的Kupffer细胞(KCs)， 会对肝脏造成组织损伤。在这里，我试图确定E11在肝脏中的细胞趋向性。我将在 体外和体内模型，以阐明这些取向在肝脏。使用hFcRnTg、mFcRn(WT)和 FcRN-/-动物将被用来了解细胞的趋向性和FcRN在感染中的作用。此外，我 想要了解这种细胞趋向性如何影响肝脏的功能。在这个目标中，我将评估是否 感染可以调节肝脏中的细胞死亡，以及感染期间肝酶是否升高，提示 肝功能不全。此外，我还试图了解肝脏对E11的先天免疫反应。我会用鼠标 缺乏I型或III型干扰素信号的模型，以评估干扰素在肝脏E11感染中的作用。 这些拟议的研究将是第一批确定E11的细胞趋向性和抗病毒反应的研究之一。 在继发性感染部位的感染，如肝脏。

PROJECT SUMMARY Enteroviruses are a significant growing public health concern. Enteroviruses, such as poliovirus, coxsackievirus B (CVB), echoviruses and enterovirus 71 (EV71), typically cause minor symptoms. However, neonates and children are particularly susceptible to severe enterovirus infections, which are characterized by neurological complications such as encephalitis, meningitis, and paralysis. In addition, neonatal infections of echovirus 11 (E11) result in liver failure, which lead to death of the neonate. These single-stranded RNA viruses are primarily transmitted through the fecal-oral route, targeting the gastrointestinal (GI) tract. After replication in the GI epithelium, these viruses disseminate into secondary target tissues such as the brain, pancreas, and liver. Many enteroviruses lack comprehensive mouse models that would allow a better understanding of pathogenesis in animals. Therefore, it is necessary to develop additional mouse models that accurately mimic the complexity of interactions in the GI epithelium as well as establishing more complete mouse models for certain enteroviruses to study pathogenesis at secondary sites of infection. Currently, only a few mouse models of E11 infection exist but they do not model infection at secondary sites such as the liver. In previous studies, we have identified a pan-echovirus receptor, the neonatal Fc receptor (FcRn). We showed that human transgenic neonatal mice expressing FcRn (hFcRnTg) were more susceptible to oral echovirus 11 (E11) infection. I have established an adult mouse model of disease where E11 infects the liver, a key site in human infection. I hypothesize that after dissemination from the GI tract, E11 infects Kupffer Cells (KCs) in the liver in an FcRn-dependent manner, resulting in tissue damage to the liver. Here, I seek to determine the cell tropism of E11 in the liver. I will use in vitro and in vivo models to elucidate these tropisms in the liver. Mouse models using hFcRnTg, mFcRn (WT), and FcRn-/- animals will be used to understand the cellular tropism and the role of FcRn in infection. Additionally, I want to understand how this cellular tropism influences functionality of the liver. In this aim, I will assess whether infection can mediate cell death in the liver and whether liver enzymes are elevated during infection, suggesting liver dysfunction. In addition, I seek to appreciate the innate immune response to E11 in the liver. I will use mouse models that are deficient in type I or III interferon signaling to assess the role of IFNs in E11 infection of the liver. These proposed studies will be one of the first to define the cellular tropism and the antiviral response to E11 infection in a secondary site of infection such as the liver.