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 针对 SARS-CoV-2 感染的获得性抗原特异性免疫反应可能是 确定 COVID-19 的结果以及 CD4 T 细胞疫苗接种的有效性和持久性。 持久、强烈的抗体反应需要帮助，主要的候选疫苗包括。 一些也可以诱导 CD8 T 细胞的形式，例如病毒载体和核酸，以及 其他形式，例如佐剂蛋白，则不能提供令人信服的证据。 病毒特异性 CD8 T 细胞的作用可能会使平衡向有利于 CD8 诱导疫苗的方向倾斜 该探索性 R21 的目标 1 和目标 2 关于 T 细胞对 SARS-CoV-2 的反应。 分别涉及上呼吸道和下呼吸道呼吸道的 CD8- 和 CD4 T 细胞反应。 上皮是 SARS-CoV-2 的主要靶组织，尤其是鼻上皮。 富含 ACE2 和 TMPRSS2 的表达，我们利用病毒进入所需的宿主分子。 联合研究员 Abuzeid 在采集鼻细胞和扩大原发鼻腔方面的经验 上皮细胞 (HNEpC) 和合作者 Greninger 在 BSL3 病毒学和 定量 RNA 测量以创建研究 T 细胞感染的上皮细胞的系统 我们利用我们的大型 COVID-19 生物库、实验室经验和其他 NIAID。 产生功能上无限量的高度狂热的 SARS-CoV-2 特异性 CD8 的资源 CD4 T 细胞具有精确已知的 HLA 限制和明确的肽靶点。 HNEpC 将被仔细表征和优化，然后我们将测量 T 细胞效应器。 功能包括杀死受感染的细胞、减少病毒后代的输出和细胞因子 在后续研究中，我们希望利用 SARS-CoV-2 遗传系统来制造。 确定候选免疫逃避基因中的突变体并将我们的研究扩展到下呼吸道 总的来说，我们努力模拟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 疫苗可能需要引发 SARS-CoV-2 特异性 T 细胞，以快速识别 SARS-CoV- 2特异性感染上呼吸道上皮细胞并停止其产生 子代病毒，以限制患者体内感染和症状的进展，以及 减少可能感染其他人的传染性病毒的传播。 应用程序中，我们将使用既定的工作方法来分离大量纯SARS- 来自康复者的 CoV-2 特异性 T 细胞并研究其发挥抗病毒作用的能力 使用鼻腔内细胞的细胞培养物，这些细胞通常在新冠肺炎期间被感染。 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