Measles virus infection of the respiratory tract

呼吸道麻疹病毒感染

基本信息

批准号：
10030808
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/10030808
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 Epithelium 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 Structure of respiratory epithelium Surface Tracheal Epithelium Vaccines Viral Viremia Virus Virus Diseases Virus Replication aerosolized 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

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.

麻疹作为全球发病率和死亡率的一个原因正在增加。麻疹病毒（MeV），病原体麻疹病原体，通过呼吸道传播，是人类传染性最强的病毒之一估计基本繁殖率 (R0) 为 12-18，这推动了对高人口水平的需求免疫力以防止疫情爆发。麻疹是一种人类疾病，但猕猴可以通过以下方式感染麻疹：与人类接触，产生模仿人类麻疹的疾病，并已有效用于研究麻疹发病机制。了解 MeV 极其高效的机载传输需要了解病毒气溶胶或飞沫接触呼吸道后感染的开始，以及病毒控制和释放的机制。长期以来，呼吸道上皮细胞被认为是最先发生的部位。 MeV 感染随后扩散至淋巴组织。然而，研究人员使用增强型绿色表达荧光蛋白 (eGFP) 的重组报告 MeV 无法检测受感染的呼吸道疾病感染猕猴后早期的上皮细胞或证明感染来自猕猴的顶端表面分化了培养物中的呼吸道上皮细胞，并推断它们没有被感染。因为培养的上皮细胞基础感染后观察到表达 eGFP 的细胞，另一种观点发现肺上皮细胞感染是通过基底外侧暴露于受感染的淋巴细胞而引发的直到病毒血症形成后才会发生。后面的这些研究得出的结论是，骨髓细胞肺部 MeV 感染的起始位点是上皮细胞，而不是上皮细胞。然而，我们的数据表明，顶端呼吸道上皮细胞的感染实际上相当有效，但接触 MeV 会导致 MeV 脱落从上皮表面产生多核巨细胞，并且使其没有可检测到的感染细胞。因此，上皮细胞对于 MeV 感染的启动和传播可能很重要。鉴定呼吸道中的易感细胞，可以非常有效地启动感染和确定 MeV 进入分化上皮细胞的机制是理解的关键高效MeV传播并使用雾化疫苗进行麻疹免疫。为了解决这个关键领域我们将利用恒河猴的体外和体内研究来确定野生型猕猴的机制 MeV和疫苗株通过以下方式感染初级分化的呼吸道上皮细胞具体目的：（1）确定原代肺泡巨噬细胞对 MeV 感染的相对易感性以及来自上呼吸道和下呼吸道的分化细胞（包括肺成纤维细胞）的培养物，树突状细胞和基底细胞、纤毛细胞和产生粘液的上皮细胞。 (2)确定所使用的宿主受体 MeV感染并诱导初级分化呼吸道上皮脱落的机制细胞在顶端表面相互作用后。 (3) 识别分化呼吸的先天反应上皮细胞对 MeV 感染的影响及其在限制病毒复制中的作用。