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

项目摘要 肠道病毒是一个重要的日益增长的公共卫生问题。肠道病毒，如脊髓灰质炎病毒、柯萨奇病毒 B（CVB）、埃可病毒和肠道病毒71（EV 71）通常引起轻微症状。然而，新生儿和 儿童特别容易受到严重的肠道病毒感染，其特征是神经系统 并发症如脑炎、脑膜炎和瘫痪。此外，新生儿感染埃可病毒11 (E11)导致肝功能衰竭，从而导致新生儿死亡。这些单链RNA病毒主要是 通过粪-口途径传播，靶向胃肠道（GI）。在GI中复制后 当这些病毒进入上皮细胞时，这些病毒传播到次级靶组织，如脑、胰腺和肝脏。许多 肠道病毒缺乏全面的小鼠模型，可以更好地了解肠道病毒的发病机制。 动物因此，有必要开发额外的小鼠模型，准确地模拟的复杂性， 以及建立更完整的某些肠道病毒的小鼠模型 研究继发感染部位的发病机制。目前，只有少数小鼠模型存在E11感染 但它们不能模拟继发部位如肝脏的感染。在以前的研究中，我们已经确定了一个 新生儿Fc受体（FcRn）。我们发现人类转基因新生小鼠 表达FcRn（hFcRnTg）的小鼠更易受口腔埃可病毒11（E11）感染。我建立了一个 成年小鼠疾病模型，其中E11感染肝脏，这是人类感染的关键部位。我假设， 从胃肠道传播，E11以FcRn依赖性方式感染肝脏中的枯否细胞（KCs）， 导致肝脏组织损伤在这里，我试图确定E11在肝脏中的细胞向性。我会用在 体外和体内模型，以阐明这些向性的肝脏。使用hFcRnTg、mFcRn（WT）和 FcRn-/-动物将用于了解细胞向性和FcRn在感染中的作用。而且我 想了解这种细胞向性如何影响肝脏的功能。为此，我将评估 感染可以介导肝脏细胞死亡，以及感染期间肝酶是否升高，这表明 肝功能障碍此外，我试图了解肝脏中对E11的先天免疫反应。我会用鼠标 缺乏I型或III型干扰素信号传导的模型，以评估IFN在肝脏E11感染中的作用。 这些拟议的研究将是第一个确定细胞向性和对E11的抗病毒反应的研究之一 继发感染部位如肝脏的感染。

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.