Dissecting the drivers of persistent SARS-CoV-2 infections

剖析 SARS-CoV-2 持续感染的驱动因素

基本信息

批准号：
10736007
负责人：
Viviana A Simon
金额：
$ 83.13万
依托单位：
ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-07-17 至 2028-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10736007
关键词：
2019-nCoV 3-Dimensional Acceleration Accounting Address Age Antibodies Antiviral Agents Area B-Lymphocytes Back Bioinformatics Biological Biological Assay Biological Models Blood COVID-19 COVID-19 detection COVID-19 pandemic COVID-19 patient Case Study Characteristics Chronic Clinical Clinical Treatment Collaborations Communicable Diseases Computerized Medical Record Data Data Set Dimensions Environment Epithelium Evolution Flow Cytometry Frequencies Funding Gender General Population Genetic Complementation Test Genetic Recombination Genomics Genotype Grant Haplotypes Health system Hospitals Human Immune Immune Evasion Immune response Immunocompromised Host Immunologics Immunology Individual Infection Interferons Knowledge Link Malignant Neoplasms Maps Medical Records Metadata Minority Molecular Molecular Virology Mutation New York City Pathogenicity Pathology Patients Peer Review Phenotype Physicians Population Positioning Attribute Predisposition Process Prone Position Property Proteins Publications RNA Recovery Research Research Personnel Resistance Resolution Resources Risk Factors Role SARS-CoV-2 infection SARS-CoV-2 variant Sampling Scientist Serum Surveillance Program T-Lymphocyte Testing Therapeutic Therapeutic Intervention Translational Research Vaccination Variant Viral Virus Work acute infection antagonist betacoronavirus chronic infection cohort demographics electronic data fitness global health insight metropolitan multidisciplinary nasopharyngeal swab novel pandemic disease pathogen patient subsets pressure prevent public health emergency risk mitigation surveillance data transmission process variants of concern viral genomics virology

项目摘要

The coronavirus disease 2019 (COVID-19) pandemic caused by the betacoronavirus “severe acute respiratory syndrome coronavirus 2” (SARS-CoV-2) represents an unprecedented public health emergency. Most patients with COVID-19 clear the virus upon resolution of the acute infection but ongoing, persistent, SARS-CoV-2 replication has been documented in immunocompromised individuals. In these chronically infected patients, recovery of replication-competent virus over several weeks to months is linked to stepwise acquisition of mutations within and outside of spike. Our preliminary data show that such prolonged intra-host viral evolution plays a role in the emergence of new, antigenically distinct, SARS-CoV-2 variants. We propose to systematically elucidate the determinants of persistent SARS-CoV-2 infections using an integrated translational research approach combining real-world clinical metadata with bioinformatics, genomics and molecular virology. We will leverage an existing large surveillance dataset covering two and a half years of SARS-CoV-2 spread in New York City going back to the beginning of the pandemic in the spring of 2020 when the NY metropolitan area emerged as one of the early epicenters of the pandemic. Specific Aim 1 will dissect the clinical features and therapeutic interventions associated with persistent SARS-CoV-2 replication using existing longitudinal data from electronic medical records. These studies will be complemented by the analysis of the B and T cell populations of persistently infected patients. Specific Aim 2 will dissect the viral genotypes representative of intra-host evolution of prolonged periods with a special emphasis on co-circulating viral variants. Specific Aim 3 will examine the phenotypic properties of persistent SARS-CoV-2 variants with an emphasis on convergent evolution within and outside of the spike region (susceptibility to neutralization, fusogenicity, spike processing and interferon antagonism). Altogether, the proposed studies address a critical knowledge gap regarding the biological drivers and viral dynamics fueling the selection of SARS-CoV-2 viral variants during persistent SARS-CoV-2 infection. This knowledge will provide the scientific basis needed to treat and prevent such chronic infections thereby limiting the emergence and spread of increasingly neutralization-resistant yet transmissible SARS-CoV-2 variants.

2019年冠状病毒病（COVID-19）由Betacoronavirus引起的“严重急性呼吸道综合征冠状病毒2英寸（SARS-COV-2）代表了前所未有的公共卫生紧急情况。大多数患者通过COVID-19解决急性感染后的病毒，但持续的，持续的SARS-COV-2 在免疫功能低下的个体中已记录了复制。在这些长期感染的患者中，在几周到几个月内恢复复制能力的病毒与逐步获取有关尖峰内外的突变。我们的初步数据表明，这种长时间的宿主内病毒演化在新的，抗原不同的SARS-COV-2变体中起作用。我们建议系统地使用集成的翻译研究阐明持续的SARS-COV-2感染的决定剂现实世界中临床元数据与生物信息学，基因组学和分子病毒学结合的方法。我们将利用现有的大型监视数据集，该数据集涵盖新的两年半的SARS-COV-2 约克市回到2020年春季纽约大都会地区的大流行成为大流行的早期中心之一。特定的目标1将剖析临床特征和使用现有的纵向数据与持续的SARS-COV-2复制相关的治疗干预措施电子病历。这些研究将通过对B和T细胞种群的分析来完成持续感染的患者。特定的目标2将剖析代表宿主内部的病毒基因型长时间的演变，特别着重于共同循环病毒变体。具体的目标3将检查持久性SARS-COV-2变体的表型特性，重点是收敛进化尖峰区域内外（神经化，融合性，尖峰加工和干扰素拮抗）。拟议的研究总共解决了有关生物驱动因素和病毒的关键知识差距在持续的SARS-COV-2感染过程中，动力学加剧了SARS-COV-2病毒变体的选择。这知识将为治疗和防止这种慢性感染所需的科学依据，从而限制越来越中和抗性但可传播的SARS-COV-2变体的出现和传播。