Measles virus infection of the respiratory tract

呼吸道麻疹病毒感染

基本信息

批准号：
10392993
负责人：
Diane E Griffin
金额：
$ 40.94万
依托单位：
JOHNS HOPKINS UNIVERSITY
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：
2020-05-04 至 2025-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10392993
关键词：
Abbreviations Address Aerosols Alveolar Macrophages Apical Area Bronchoalveolar Lavage Cell Culture Techniques Cell Differentiation process Cells Chimeric Proteins Contracts Cyclophilins Data Dendritic Cells Disease Disease Outbreaks Epithelial Epithelial Cells Exposure to Extracellular Matrix Family Fibroblasts Fluorescent in Situ Hybridization Genome Germ Cells Giant Cells Hemagglutinin Human Immunity Immunization In Vitro Infection Interferons Knowledge Lipids Lower respiratory tract structure Lung Lymphocyte Lymphoid Tissue Macaca Macaca mulatta Measles Measles Vaccine Measles virus Morbidity - disease rate Morbillivirus Mucous body substance Myeloid Cells Nasal Epithelium Nucleocapsid Proteins Paramyxovirus Pathogenesis Peptides Population Predisposition Proteins RNA Viruses Recombinants Reporter Research Personnel Research Proposals Resistance Respiration Respiratory System Respiratory Tract Infections Respiratory syncytial virus Role Route Site Sphingosine-1-Phosphate Receptor Surface Tracheal Epithelium Vaccines Viral Viremia Virus Virus Diseases Virus Replication aerosolized airway epithelium attenuated measles virus enhanced green fluorescent protein human disease in vivo mortality parainfluenza virus prevent receptor reproductive respiratory respiratory infection virus response sphingosine 1-phosphate transmission process viral transmission

Abbreviations Address Aerosols Alveolar Macrophages Apical Area Bronchoalveolar Lavage Cell Culture Techniques Cell Differentiation process Cells Chimeric Proteins Contracts Cyclophilins Data Dendritic Cells Disease Disease Outbreaks Epithelial Epithelial Cells Exposure to Extracellular Matrix Family Fibroblasts Fluorescent in Situ Hybridization Genome Germ Cells Giant Cells Hemagglutinin Human Immunity Immunization In Vitro Infection Interferons Knowledge Lipids Lower respiratory tract structure Lung Lymphocyte Lymphoid Tissue Macaca Macaca mulatta Measles Measles Vaccine Measles virus Morbidity - disease rate Morbillivirus Mucous body substance Myeloid Cells Nasal Epithelium Nucleocapsid Proteins Paramyxovirus Pathogenesis Peptides Population Predisposition Proteins RNA Viruses Recombinants Reporter Research Personnel Research Proposals Resistance Respiration Respiratory System Respiratory Tract Infections Respiratory syncytial virus Role Route Site Sphingosine-1-Phosphate Receptor Surface Tracheal Epithelium Vaccines Viral Viremia Virus Virus Diseases Virus Replication aerosolized airway epithelium attenuated measles virus enhanced green fluorescent protein human disease in vivo mortality parainfluenza virus prevent receptor reproductive respiratory respiratory infection virus response sphingosine 1-phosphate transmission process viral transmission

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项目摘要

Measles is increasing as a cause of morbidity and mortality worldwide. Measles virus (MeV), the causative agent of measles, is spread by the respiratory route and is one of the most highly infectious viruses of humans with an estimated basic reproductive rate (R0) of 12-18 that drives the need for high levels of population immunity to prevent outbreaks. Measles is a human disease, but macaques can contract measles through contact with humans, develop disease that mimics human measles and have been effectively used for studies of measles pathogenesis. Understanding the extremely efficient airborne transmission of MeV requires knowledge of both the initiation of infection after viral aerosol or droplet contact with the respiratory tract and mechanisms of virus control and release. Respiratory epithelial cells were long assumed to be the first site of MeV infection with subsequent spread to lymphoid tissue. However, investigators using enhanced green fluorescent protein (eGFP)-expressing recombinant reporter MeVs were not able to detect infected respiratory epithelial cells early after infection of macaques or to demonstrate infection from the apical surface of differentiated respiratory epithelial cells in culture and deduced that they had not become infected. Because eGFP-expressing cells were observed after basal infection of cultured epithelial cells, an alternate view emerged that lung epithelial cell infection is initiated through basolateral exposure to infected lymphocytes and does not occur until after the viremia is established. These latter studies have concluded that myeloid cells rather than epithelial cells are the initial sites of MeV infection in the lung. However, our data show that apical infection of respiratory epithelial cells is actually quite efficient, but exposure to MeV induces shedding of MeV- producing multinucleated giant cells from the epithelial surface and leaves it without detectable infected cells. Therefore, epithelial cells may be important for the initiation as well as dissemination of MeV infection. Identification of the susceptible cells in the respiratory tract that allow for very efficient initiation of infection and determination of the mechanism of MeV entry into differentiated epithelial cells are key to understanding efficient MeV transmission and use aerosolized vaccine for measles immunization. To address this critical area we will use in vitro and in vivo studies of rhesus macaques to identify the mechanisms by which both wild type and vaccine strains of MeV infect primary differentiated respiratory tract epithelial cells through the following specific aims: (1) Determine the relative susceptibility to infection with MeV of primary alveolar macrophages and cultures of differentiated cells from the upper and lower respiratory tract that include lung fibroblasts, dendritic cells and basal, ciliated and mucous-producing epithelial cells. (2) Determine the host receptors used and mechanisms by which MeV infects and induces shedding of primary differentiated respiratory epithelial cells after interaction at the apical surface. (3) Identify the innate responses of differentiated respiratory epithelial cells to MeV infection and their role(s) in restricting virus replication.

麻疹正在增加，这是全球发病率和死亡率的原因。麻疹病毒（MEV），原因麻疹剂是通过呼吸道传播的，是人类最高度感染性的病毒之一估计的基本生殖率（R0）为12-18，这推动了对高水平人口的需求防止爆发的免疫力。麻疹是一种人类疾病，但猕猴可以通过与人类接触，发展模仿人麻疹并有效用于研究的疾病麻疹发病机理。了解MEV的极其有效的机载传输需要了解病毒气溶胶后感染的开始或与呼吸道接触的知识病毒控制和释放的机制。长期以来，呼吸上皮细胞被认为是 MEV感染随后扩散到淋巴组织。但是，调查人员使用增强的绿色荧光蛋白（EGFP）表达重组记者MEV无法检测到感染的呼吸道猕猴感染后早期上皮细胞或从分化的培养中呼吸道上皮细胞，并推断出它们没有被感染。因为在培养的上皮细胞基础感染后观察到表达EGFP的细胞，这是一种替代视图出现的是，肺上皮细胞感染是通过基底外侧暴露于感染的淋巴细胞和直到建立病毒血症之后才发生。这些后者的研究得出的结论是髓样细胞而不是上皮细胞是肺中MEV感染的初始部位。但是，我们的数据表明顶端呼吸上皮细胞的感染实际上是非常有效的，但暴露于MEV会引起Mev-的脱落。从上皮表面产生多核巨细胞，并将其留而没有可检测到的感染细胞。因此，上皮细胞可能对MEV感染的启动和传播可能很重要。识别呼吸道中易感细胞，该细胞允许非常有效地感染和确定MEV进入分化上皮细胞的机制是理解的关键有效的MEV传播并使用雾化的疫苗进行麻疹免疫。解决这个关键领域我们将在体外和体内猕猴研究中识别两种野生型的机制 MEV的疫苗菌株通过以下具体目的：（1）确定用MEV的原发性肺泡巨噬细胞感染的相对敏感性以及从包括肺成纤维细胞的上和下呼吸道分化细胞的培养物，树突状细胞和基础，纤毛和粘液产生的上皮细胞。（2）确定所使用的宿主受体 MEV感染并诱导主要分化呼吸道上皮的机制和机制在顶部表面相互作用后的细胞。（3）确定分化呼吸系统的先天反应 MEV感染的上皮细胞及其在限制病毒复制中的作用。