权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

C19 SARS-CoV-2-specific T cells in the infected nasel epithelium

受感染鼻上皮中的 C19 SARS-CoV-2 特异性 T 细胞

基本信息

批准号：
10285229
负责人：
David M Koelle
金额：
$ 26.47万
依托单位：
UNIVERSITY OF WASHINGTON
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-06-15 至 2023-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10285229
关键词：
2019-nCoV ACE2 Adjuvant Adult Respiratory Distress Syndrome Anatomy Antibody Response Antigens Antiviral Agents Antiviral Response Applications Grants Area Attenuated Avidity CD4 Positive T Lymphocytes CD8-Positive T-Lymphocytes CD8B1 gene COVID-19 COVID-19 vaccine Cell Communication Cell Culture Techniques Cell Death Cell Line Cells Complex Containment Curette Data Daughter Disease Environment Epithelial Epithelial Cells Epitopes Equilibrium Follow-Up Studies Genes Genetic Harvest Home Human Immune Immune Evasion Immune response In Vitro Infection Inferior nasal concha Inflammatory Influenza vaccination Lower respiratory tract structure Measurement Measures Medical Methods Modeling Nasal Epithelium Nasal cavity National Institute of Allergy and Infectious Disease Nose Nucleic Acids Organ Organoids Outcome Output Patients Peptides Peripheral Blood Mononuclear Cell Persons Physiological Pneumonia Production Proteins RNA Reagent Research Personnel Resources Respiratory System SARS-CoV-2 infection Site Specificity Speed Structure of respiratory epithelium Symptoms System T cell response T-Lymphocyte TMPRSS2 gene Technology Time Tissues Triad Acrylic Resin Upper respiratory tract Vaccination Vaccines Viral Viral Proteins Viral Vector Virus Virus Replication Work acquired immunity biobank cohort cytokine cytotoxicity effector T cell experience in vivo laboratory experience mutant neutralizing antibody pathogen response severe COVID-19 tool vaccine candidate virology

项目摘要

Summary The acquired, antigen-specific immune response to SARS-CoV-2-infection is likely central to determining the outcome of COVID-19 and the efficacy and durability of vaccination. CD4 T cell help is required for lasting, avid antibody responses. The leading vaccine candidates include some formats that can also induce CD8 T cells, such as viral vectors and nucleic acids, and other formats such as adjuvanted protein that cannot. Compelling evidence for an antiviral effects of virus-specific CD8 T cells could tilt the balance in favor of CD8-eliciting vaccine platforms. Aim 1 and Aim 2 of this exploratory R21 on the T cell response to SARS-CoV-2 concern CD8- and CD4 T cell responses, respectively. Upper and lower airway respiratory epithelium are the primary target tissues for SARS-CoV-2. The nasal epithelium is particularly rich in expression of ACE2 and TMPRSS2, host molecules required for viral entry. We leverage Co-Investigator Abuzeid’s experience in harvesting nasal cells and expanding primary nasal epithelial cells (HNEpC) and Collaborator Greninger’s expertise in BSL3 virology and quantitative RNA measurement to create systems to study T cell-infected epithelial cell interactions in vitro. We use our large COVID-19 biobank, in-lab experience, and other NIAID resources to generate functionally unlimited amounts of highly avid SARS-CoV-2-specific CD8 and CD4 T cells with precisely known HLA restriction and defined peptide targets. Infection of HNEpC will be carefully characterized and optimized. We will then measure T cell effector functions including the killing of infected cells, reduction of viral progeny output, and cytokine release. In follow-up studies, we hope to leverage SARS-CoV-2 genetic systems to make defined mutants in candidate immune evasion genes and extend our studies to lower respiratory tract cells and organoids. Overall, we strive to model important interactions between immune cells and the SARS-CoV-2 infected respiratory tract. Relevance Vaccines may need to elicit SARS-CoV-2 specific T cells that can quickly recognize SARS-CoV- 2-specific infected upper respiratory tract epithelial cells and shut down their production of progeny virus, to both limit the progression of infection and symptoms within patients, and reduce the shedding of infectious virus that may infect other persons. In this R21 grant application, we will use established, working methods to isolate large quantities of pure SARS- CoV-2-specific T cells from recovered persons and study their ability to exert anti-viral effects using cell cultures of the cells that line the nasal cavity that are normally infected during COVID- 19.

总结