Mapping spatiotemporal dynamics during enterovirus infection across cells and tissues

绘制肠道病毒跨细胞和组织感染过程中的时空动态

基本信息

批准号：
10450337
负责人：
Raul Andino
金额：
$ 86.87万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-03-10 至 2027-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10450337
关键词：
Acute Adolescent Affect Alleles Animal Model Antiviral Agents Antiviral Response Atlases Attenuated Biological Brain Stem CRISPR/Cas technology Cardiomyopathies Cells Clinical Coxsackie B Viruses Data Data Set Development Diabetes Mellitus Disease Encephalitis Enterovirus Enterovirus Infections Evolution Family Genes Genetic Determinism Genetic Structures Genetic Transcription Genomics Goals Hand, Foot and Mouth Disease Heart Diseases Hospitalization Human Human poliovirus Immune response Individual Infant Infection Innate Immune Response Interferon Type I Interferon-alpha Interferon-beta Interferons Intervention Knowledge Lesion Life Link Maps Measures Medical Meningitis Methods Mus Mutation Myocarditis Natural Immunity Nerve Tissue Neurologic Symptoms Pancreatitis Paralysed Pathogenesis Pathogenicity Pathway interactions Pericarditis Pharmaceutical Preparations Phylogenetic Analysis Population Population Dynamics Population Genetics Primary Infection Process Respiratory Signs and Symptoms Reverse engineering Role Severities Shapes Signal Transduction Source Specificity Structure Testing Tissue-Specific Gene Expression Tissues Tropism United States Vaccines Viral Virulence Virus Virus Diseases Virus Replication cell type deep learning deep sequencing emerging pathogen experimental study in vivo innovative technologies insight mathematical model mouse model mutant neonatal sepsis novel pressure prevent respiratory response single cell analysis single-cell RNA sequencing spatiotemporal tissue tropism transcriptome transcriptomics vaccine development virus genetics virus host interaction

项目摘要

Project Summary Human enterovirus (HEV) infections primarily affect infant and adolescent populations, causing a wide range of clinical manifestations that commonly include respiratory illness and mucocutaneous lesions, or hand, foot and mouth disease. In some cases, the infection is life- threatening. The clinical manifestations are a function of their tropism. For example, some HEVs, including EV-A71 and EV-D68, are associated with serious neurological symptoms due to invasion and damage of central nervous tissues. Others, such CVB3, are implicated in respiratory symptoms and cardiomyopathy. This proposal aims to take an integrative approach to understand how tissues, and cells within these tissues, respond to infection by CVB3 and the emerging pathogens EV-D68 and EV-A71. We will determine the temporal and spatial dynamics of HEV infection using recent advances in genomics: (i) We will profile single-cell transcriptomes to quantify viral replication levels and the host response to infection across cells and tissues over the course of infection. (ii) Given that intra-host adaptation appears to be important in infection, in parallel, we will map the mutational spectrum of the replicating viruses using a novel ultra-deep sequencing approach. We will use new innovative technologies, such as ultra-deep virus population sequencing, deep learning and single-cell analysis to increase our basic understanding of the pathogenesis of enteroviruses A, B and D. Finally, given that innate immunity is a major determinant of tissue tropism, we will use mice with deletions of specific type-I IFN subtypes to determine the significance of interferon diversity in controlling HEV infections. These data will enable us to determine cell types that HEVs infect, the response that the host mounts against them in each cell and tissue, and the viral mutants that emerge in different tissues. Understanding pathogenesis is critically needed for developing effective and broadly-acting countermeasures and to inform the development of effective and broad-spectrum vaccines and antiviral compounds.

项目摘要人肠病毒（HEV）感染主要影响婴儿和青少年人群，导致通常包括呼吸系统疾病和粘膜皮肤病变，或手，脚和口腔疾病。在某些情况下，感染是生命的威胁。临床表现是其对流的函数。例如，有些HEV，包括EV-A71和EV-D68在内，与严重的神经系统症状有关中枢神经组织的侵袭和损害。其他CVB3则与呼吸有关症状和心肌病。该建议旨在采用综合方法来理解这些组织中的组织和细胞如何应对CVB3和出现的感染病原体EV-D68和EV-A71。我们将确定HEV的时间和空间动力学使用最新基因组学进展的感染：（i）我们将单细胞转录组概述量化病毒复制水平以及跨细胞和组织感染的宿主反应感染过程。（ii）鉴于主宿内适应在感染中似乎很重要，同时，我们将使用新型的超深度绘制复制病毒的突变光谱测序方法。我们将使用新的创新技术，例如超深病毒人口测序，深度学习和单细胞分析以增加我们的基本理解肠病毒A，B和D的发病机理，最后，鉴于先天免疫是主要的组织对流的决定因素，我们将使用具有特定I型IFN亚型缺失的小鼠到确定干扰素多样性在控制HEV感染中的重要性。这些数据将使我们能够确定HEV感染的细胞类型它们在每个细胞和组织中，以及在不同组织中出现的病毒突变体。理解发病机理需要开发有效和广泛作用的对策并告知有效和广谱疫苗的开发和抗病毒化合物。