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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.

项目概要肠道病毒是一个日益严重的公共卫生问题。肠道病毒，例如脊髓灰质炎病毒、柯萨奇病毒 B (CVB)、埃可病毒和肠道病毒 71 (EV71) 通常会引起轻微症状。然而，新生儿和儿童特别容易受到严重肠道病毒感染，其特点是神经系统疾病脑炎、脑膜炎、瘫痪等并发症。此外，新生儿感染埃可病毒11 (E11) 导致肝衰竭，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，针对胃肠道（GI）。在 GI 中复制后这些病毒通过上皮细胞传播到次要目标组织，例如大脑、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来准确模拟复杂性胃肠道上皮中的相互作用以及针对某些肠道病毒建立更完整的小鼠模型研究继发感染部位的发病机制。目前，只有少数E11感染小鼠模型存在但它们并不能模拟肝脏等次要部位的感染。在之前的研究中，我们已经确定了一个泛埃可病毒受体，新生儿 Fc 受体 (FcRn)。我们证明人类转基因新生小鼠表达 FcRn (hFcRnTg) 的人更容易受到口腔埃可病毒 11 (E11) 感染。我已经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。我假设之后从胃肠道传播，E11 以 FcRn 依赖性方式感染肝脏中的库普弗细胞 (KC)，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。我将用在体外和体内模型来阐明肝脏中的这些趋向性。使用 hFcRnTg、mFcRn (WT) 和 FcRn-/- 动物将用于了解 FcRn 在感染中的细胞向性和作用。另外，我想要了解这种细胞趋向性如何影响肝脏的功能。为了这个目标，我将评估是否感染可以介导肝脏中的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首批定义 E11 的细胞向性和抗病毒反应的研究之一继发感染部位（例如肝脏）的感染。