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

定义新生儿 Fc 受体在埃可病毒 II 感染新模型中的作用

基本信息

批准号：
10375352
负责人：
Alexandra Wells
金额：
$ 3.32万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-01 至 2022-04-03
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10375352
关键词：
Acute Liver Failure Adult Animals Antiviral Agents Antiviral Response Birth Blood Brain Cell Death Cells Cellular Tropism Cessation of life Child Childhood Clinical Coxsackie B Viruses Data Development Disease Disease model Echo Viruses Echovirus Infections Ectopic Expression Encephalitis Enterovirus Enterovirus 71 Enterovirus Infections Enzymes Exanthema Fc Receptor Functional disorder Gastrointestinal tract structure Germ Cells Hepatocyte Human Human poliovirus Immunoglobulin G In Vitro Infection Ingestion Innate Immune Response Interferons Intestines Kupffer Cells Lead Liver Liver Dysfunction Liver Failure Mediating Meningitis Minor Modeling Mothers Mus Neurologic Oral Pancreas Paralysed Passive Immunity Pathogenesis Physiological Placenta Population Pregnancy Primary Infection Public Health RNA Viruses Research Role Route Sepsis Signal Transduction Site Small Intestines Specificity Subgroup Symptoms Therapeutic Tissues Transgenic Mice Transgenic Organisms Tropism United States Virus acute flaccid myelitis cell type enteric infection gastrointestinal epithelium human disease in vivo Model insight liver function liver infection liver injury mouse model neonatal Fc receptor neonatal infection neonatal mice neonate novel poliovirus receptor receptor response therapeutically effective

项目摘要

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.

项目摘要肠病毒是公共卫生的重大关注点。肠病毒，例如脊髓灰质炎病毒，coxsackievivirus B（CVB），回声病毒和肠病毒71（EV71）通常会引起较小的症状。但是，新生儿和儿童特别容易受到严重的肠病毒感染的影响，其特征是神经系统并发症，例如脑炎，脑膜炎和麻痹。此外，回波病毒的新生儿感染11 （E11）导致肝衰竭，导致新生儿死亡。这些单链RNA病毒主要是通过粪便途径传播，靶向胃肠道（GI）。在GI中复制后这些病毒上皮将大脑，胰腺和肝脏等次要靶组织传播到二次靶向组织中。许多肠病毒缺乏全面的小鼠模型，可以更好地理解发病机理动物。因此，有必要开发其他鼠标模型，以准确模仿 GI上皮中的相互作用，并为某些肠病毒建立更完整的鼠标模型在感染的次要部位研究发病机理。目前，仅存在少数E11感染的鼠标模型但是它们不会在诸如肝脏之类的次要部位建模感染。在以前的研究中，我们已经确定了泛病毒受体，新生儿FC受体（FCRN）。我们表明人类转基因新生儿小鼠表达FCRN（HFCRNTG）更容易受到口服回声病毒11（E11）感染的影响。我已经建立了成年小鼠疾病模型，其中E11感染了人类感染的关键部位肝脏。我假设这是从胃肠道传播，E11以FCRN依赖性的方式感染了肝脏中的库普弗细胞（KC）导致组织损害肝脏。在这里，我试图确定肝脏中E11的细胞向潮流。我会用体外和体内模型，阐明了肝脏中的这些向性。使用HFCRNTG，MFCRN（WT）和 FCRN - / - 动物将用于了解细胞的向流和FCRN在感染中的作用。另外，我想了解这种细胞向性能如何影响肝脏的功能。在此目标中，我将评估是否感染可以介导肝脏中的细胞死亡以及在感染过程中是否升高肝酶，表明肝功能障碍。此外，我试图欣赏肝脏中对E11的先天免疫反应。我将使用鼠标 I型或III型干扰素信号不足以评估IFN在肝脏E11感染中的作用的模型。这些拟议的研究将是最早定义细胞托管和对E11的抗病毒反应的研究之一。感染中感染的感染，例如肝脏。