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

• 批准号: 10430281
• 负责人: David M Koelle
• 金额: $ 22.06万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-06-15 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10430281
• 关键词: 2019-nCoV; ACE2; Acute Respiratory Distress Syndrome; Adjuvant; Anatomy; Antibody Response; Antigens; 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; 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; airway epithelium; biobank; cohort; cytokine; cytotoxicity; effector T cell; experience; in vivo; laboratory experience; mutant; neutralizing antibody; pathogen; response; severe COVID-19; tool; vaccine candidate; vaccine platform; virology

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.

概括 获得的，抗原特异性的对SARS-COV-2感染的免疫反应可能是 确定Covid-19的结果以及疫苗接种的效率和耐用性。 CD4 T细胞 持久，狂热的抗体反应需要帮助。领先的候选疫苗包括 一些也可以诱导CD8 T细胞的格式，例如病毒载体和核酸，以及 其他格式，例如无法调整的蛋白质。令人信服的抗病毒证据 病毒特异性CD8 T细胞的影响可以倾斜平衡，有利于CD8吸收疫苗 平台。 AIM 1和AIM 2在T细胞对SARS-COV-2的响应中的AIM 2 分别关注CD8和CD4 T细胞反应。上和下气道呼吸道 上皮是SARS-COV-2的主要目标时间。鼻上皮特别是 富含ACE2和TMPRSS2的表达，病毒进入所需的宿主分子。我们利用 共同投资者Abuzeid在收集鼻细胞和扩大原发性鼻细胞方面的经验 上皮细胞（HNEPC）和合作者Gringer在BSL3病毒学和 定量RNA测量以创建用于研究T细胞感染的上皮细胞的系统 体外相互作用。我们使用大型Covid-19-19 生成功能无限量的高度狂热SARS-COV-2特异性CD8的资源 和具有精确已知的HLA限制和定义的肽靶标的CD4 T细胞。感染 HNEPC将被仔细表征和优化。然后，我们将测量T细胞效应器 功能，包括杀死感染细胞，病毒进度的减少和细胞因子的功能 发布。在后续研究中，我们希望利用SARS-COV-2遗传系统使 候选免疫进化基因中定义的突变体，并将我们的研究扩展到下呼吸道 区域细胞和类器官。总体而言，我们努力建模免疫之间的重要相互作用 细胞和SARS-COV-2感染的呼吸道。 关联 疫苗可能需要引起SARS-COV-2特异性T细胞，以迅速识别SARS-COV- 2特异性感染的上呼吸道上皮细胞，并关闭其生产 后代病毒，以限制患者内感染和症状的进展，以及 减少可能感染其他人的传染病的脱落。在R21赠款中 应用，我们将使用已建立的工作方法来隔离大量的纯SARS- COV-2特异性的T细胞来自恢复的人并研究其发挥抗病毒作用的能力 使用在鼻腔中通常被感染的鼻腔细胞的细胞培养物 19。

项目成果

T cell response to intact SARS-CoV-2 includes coronavirus cross-reactive and variant-specific components.

• DOI: 10.1172/jci.insight.158126
• 发表时间: 2022-03-22
• 期刊: JCI insight
• 影响因子: 8
• 作者: Jing L;Wu X;Krist MP;Hsiang TY;Campbell VL;McClurkan CL;Favors SM;Hemingway LA;Godornes C;Tong DQ;Selke S;LeClair AC;Pyo CW;Geraghty DE;Laing KJ;Wald A;Gale M Jr;Koelle DM
• 通讯作者: Koelle DM

Diminished humoral and cellular responses to SARS-CoV-2 vaccines in patients with chronic lymphocytic leukemia.

• DOI: 10.1182/bloodadvances.2022009164
• 发表时间: 2023-09-12
• 期刊: Blood advances
• 影响因子: 7.5
• 作者: Ujjani C;Gooley TA;Spurgeon SE;Stephens DM;Lai C;Broome CM;O'Brien S;Zhu H;Laing KJ;Winter AM;Pongas G;Greninger AL;Koelle DM;Siddiqi T;Davids MS;Rogers KA;Danilov AV;Sperling A;Tu B;Sorensen T;Launchbury K;Burrow CJ;Quezada G;Hill JA;Shadman M;Thompson PA
• 通讯作者: Thompson PA