Characterization of the T-cell Response to Human Norovirus Infection

T 细胞对人类诺如病毒感染反应的表征

基本信息

批准号：
10042789
负责人：
Michael Daniel Keller
金额：
$ 8.93万
依托单位：
CHILDREN'S RESEARCH INSTITUTE
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-06-01 至 2022-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10042789
关键词：
Address Adenoviruses Adoptive Immunotherapy Adoptive Transfer Alleles Antibodies Antigens Antiviral Agents Antiviral Therapy Blood Blood Group Antigens Blood donor Capsid Proteins Cell Therapy Cells Child Chronic Chronic diarrhea Clinical Clinical Trials Collaborations Cytomegalovirus Data Development Disease Effector Cell Enteral Epidemic Epitope Mapping Epitopes Flow Cytometry France Future Gastroenteritis Genbank Genotype Goals Hematopoietic Stem Cell Transplantation Hepatotoxicity Hospitals Human Human Herpesvirus 4 Immunity Immunocompromised Host Immunoglobulins Immunologic Deficiency Syndromes Immunotherapy Individual Infection Infusion procedures Interferon Type II Knowledge Life MHC Class I Genes Maps Messenger RNA Methods Morbidity - disease rate National Institute of Allergy and Infectious Disease Norovirus Patient Transfer Patients Peptide Hydrolases Peptides Prevalence RNA Viruses Reporting Safety Spottings Stains T cell response T-Lymphocyte T-Lymphocyte Epitopes T-Lymphocyte Subsets Testing Therapeutic Therapy trial Transcript United States National Institutes of Health Vaccines Variant Viral Viral Genome Viral Proteins Virus Virus Diseases Viviparous-1 protein anti-viral efficacy congenital immunodeficiency cross reactivity cytokine cytotoxic CD8 T cells design effector T cell improved in silico insight nano-string new therapeutic target next generation sequencing novel prediction algorithm response seropositive vaccine development vaccine trial wasting

项目摘要

Abstract Chronic norovirus infection can cause chronic diarrhea and wasting in immunocompromised patients, including those undergoing hematopoietic stem cell transplantation and with primary immunodeficiency disorders. There are currently no available therapies to treat norovirus. Our preliminary data demonstrates that healthy individuals have T cell immunity against norovirus, and that identified viral epitopes in antigens NS6 and VP1 are well conserved across viral genotypes. The overarching goal of this proposal is the development of a novel treatment for chronic norovirus infection in patients undergoing HSCT. In our previous study, we demonstrated safety and potential efficacy of virus-specific T cells targeting CMV, EBV, and adenovirus as well as the feasibility of this approach. Knowledge of T-cell response to norovirus could enable future trials of adoptive immunotherapy with NSTs, which represents a novel antiviral therapy that could provide long-term protection against norovirus. To classify the T-cell response against norovirus we now propose to take blood from the healthy donors and expand and enrich the norovirus-specific T cells (NSTs) present in donors' blood, followed by extensive characterization of the function of NSTs. We hypothesize that the infusion of NSTs will be safe and effective against norovirus infections in patients post HSCT, and will restore lasting immunity against norovirus. We further hypothesize that norovirus epitopes will correlate with expansion of T cells recognizing immunodominant viral epitopes, which will correspond to stable regions of the viral genome. Through this study, we will address the following specific aims: 1) To determine whether norovirus specific T cells recognize a broad number of MHC Class I and class II restricted epitopes, and 2) To evaluate whether norovirus epitope specific T cells are cross-reactive with a broad panel of isolates encompassing multiple viral strains. Collectively, these aims will identify the range and stability of norovirus epitopes. Completion of this study could provide a novel antiviral therapy which could reduce virus-associated morbidity in HSCT, and will guide future cellular therapy and vaccine trials targeting enteric viruses.

抽象的慢性诺如病毒感染可导致免疫功能低下患者慢性腹泻和消瘦，包括接受造血干细胞移植并患有原发性免疫缺陷病的人。那里目前尚无治疗诺如病毒的可用疗法。我们的初步数据表明，健康个体具有针对诺如病毒的 T 细胞免疫力，并在抗原 NS6 和 VP1 中识别出病毒表位在病毒基因型中都非常保守。该提案的总体目标是开发一种新颖的接受 HSCT 患者慢性诺如病毒感染的治疗。在我们之前的研究中，我们证明了针对 CMV、EBV 和腺病毒的病毒特异性 T 细胞的安全性和潜在功效以及这种方法的可行性。了解 T 细胞对诺如病毒的反应可以使未来的收养试验成为可能 NST 免疫疗法，代表一种可以提供长期保护的新型抗病毒疗法对抗诺如病毒。为了对针对诺如病毒的 T 细胞反应进行分类，我们现在建议从健康的捐献者，并扩大和丰富捐献者血液中存在的诺如病毒特异性 T 细胞 (NST)，然后通过对 NST 功能的广泛表征。我们假设 NST 的输注是安全的对造血干细胞移植后患者的诺如病毒感染有效，并将恢复对诺如病毒的持久免疫力诺如病毒。我们进一步假设诺如病毒表位将与识别 T 细胞的扩增相关免疫显性病毒表位，对应于病毒基因组的稳定区域。通过这个研究中，我们将解决以下具体目标：1）确定诺如病毒特异性T细胞是否识别大量 MHC I 类和 II 类限制性表位，以及 2) 评估诺如病毒表位是否特定的 T 细胞与包含多种病毒株的广泛分离株发生交叉反应。总的来说，这些目标将确定诺如病毒表位的范围和稳定性。完成这项研究可以提供一种新型抗病毒疗法，可以降低 HSCT 中病毒相关的发病率，并将指导未来针对肠道病毒的细胞疗法和疫苗试验。