Defining astrovirus-specific T cell responses

定义星状病毒特异性 T 细胞反应

基本信息

批准号：
10667003
负责人：
Megan T Baldridge
金额：
$ 19.53万
依托单位：
WASHINGTON UNIVERSITY
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：
2023-03-01 至 2025-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10667003
关键词：
Acute Adoptive Transfer Age Alleles Animal Model Antibody Response Antiviral Agents Astrovirus B-Lymphocytes Blood Bone Marrow Transplantation CD3 Antigens CD8-Positive T-Lymphocytes Cattle Cell Therapy Cell physiology Cells Cellular Tropism Childhood Chronic Clinical Cytotoxic T-Lymphocytes Data Development Diarrhea Elements Encephalitis Enteral Epithelial Cells Epitopes Family suidae Foundations Future Gastroenteritis Genetic Recombination Genomics Goals Grant High Prevalence Human Immune Immune response Immunity Immunocompetent Immunocompromised Host Immunodeficient Mouse Immunodominant Epitopes Immunologic Deficiency Syndromes Immunologics Impairment Individual Infant Infection Innate Immune Response Interferons Intestines Investigation MHC Class I Genes Memory Meningitis Methods Modeling Mucosal Immune Responses Mus Norovirus Organ Pathogenesis Peptide Library Peripheral Blood Mononuclear Cell Phenotype Phylogenetic Analysis Protocols documentation RNA Viruses Reagent Reporting Research Resolution Risk Role Sampling Seroprevalences Small Intestines Spleen Splenocyte Stomach T cell response T cell therapy T-Lymphocyte T-Lymphocyte Epitopes Therapeutic Tissues Tropism Turkey bird Vaccination Vaccine Design Vaccine Therapy Vaccines Viral Virus Virus Diseases Wild Type Mouse Work Zoonoses adaptive immunity anti-viral efficacy chronic infection combat flu immunoregulation in vivo insight intestinal epithelium mesenteric lymph node mouse model older patient pathogen pathogenic virus peptide I prevent screening tool virus development virus tropism

项目摘要

PROJECT SUMMARY/ABSTRACT Human astroviruses (HAstVs) are a global cause of pediatric gastroenteritis, and can cause disseminated infection in immunocompromised hosts. Seroprevalence studies indicate almost universal HAstV infection during childhood. Despite their clinical importance, HAstVs are highly understudied in part due to the lack of a well- defined small animal model. Murine astrovirus (muAstV), which shares numerous genomic and phenotypic features with HAstVs, causes chronic infection in immunodeficient models and has begun to provide important insights into innate and adaptive immune regulation of AstV pathogenesis in vivo. Preliminary data indicates that CD8+ T cells are critical for clearance of chronic muAstV. However, to date functional and phenotypic features of the CD8+ T cell response remain uncharacterized for both HAstV and muAstV. Further, the specific viral epitopes targeted by CD8+ T cells remain to be delineated for both HAstV and muAstV. The definition of immunodominant CD8+ T cell epitopes will facilitate characterization of AstV-specific T cell functions in vivo and reveal key viral epitopes to target for future vaccines and cellular therapies. Overlapping peptide libraries will be used for ex vivo screening of immunodominant muAstV CD8+ T cell epitopes by well- established protocols, with the goal of developing MHC class I peptide tetramers to track muAstV-specific CD8+ T cells. Two phenotypically-distinct muAstV strains, with one causing acute self-limited infection and the other causing chronic infection in immunocompetent mice, will be leveraged to define effector and memory muAstV- specific CD8+ T cell phenotypes and functionality across multiple tissues. These studies, to be conducted in established in vivo mouse models, will reveal whether functionally suboptimal CD8+ T cell responses contribute to impaired clearance of some viral strains. Finally, human peripheral blood mononuclear cells from donors carrying an MHC class I allele associated with protection from HAstV will be used to identify immunodominant HAstV CD8+ T cell epitopes, permitting development of tetramers to characterize HAstV-specific CD8+ T cell phenotypes across a variety of donors with this common allele. These studies are highly appropriate for the R21 grant mechanism, as they involve development of critical tools for immunological studies using methods that have not yet been applied towards AstVs. Completion of this proposal will both provide key insights into the cellular immune response against AstVs and develop tetramer reagents to be used for future definition of T cell responses following natural infection and vaccination. Further, immunodominant epitopes identified will represent important targets for vaccines and cellular therapies against these clinically important enteric viral pathogens.

项目摘要/摘要人星座病毒（HASTV）是小儿胃炎的全球原因，可能导致传播免疫功能低下的宿主感染。血清阳性研究表明几乎普遍的HASTV感染童年。尽管它们的临床重要性，但HASTV还是高度研究了，部分原因是缺乏良好的定义的小动物模型。鼠星际病毒（MUASTV），具有许多基因组和表型具有HASTV的功能，引起免疫缺陷模型中的慢性感染，并已开始提供重要的对体内ASTV发病机理的先天和适应性免疫调节的见解。初步数据表明 CD8+ T细胞对于清除慢性MUASTV至关重要。但是，迄今为止的功能和表型特征对于HASTV和MUASTV，CD8+ T细胞反应的响应均未表征。此外，特定病毒 CD8+ T细胞靶向的表位仍然待描绘HASTV和MUASTV。免疫主导CD8+ T细胞表位的定义将促进ASTV特异性T的表征细胞功能在体内并揭示了关键的病毒表位，以靶向未来的疫苗和细胞疗法。重叠肽库将用于在体内筛查免疫主导MUASTV CD8+ T细胞表位，并通过良好建立的协议，目的是开发MHC I类肽四聚体以跟踪MUASTV特异性CD8+ T细胞。两种表型固定的MUASTV菌株，一种引起急性自限感染，另一种引起在免疫能力小鼠中引起慢性感染，将杠杆定义效应器和记忆穆斯特维（Muastv-）多个组织的特定CD8+ T细胞表型和功能。这些研究，将在建立在体内鼠标模型中，将揭示功能次优的CD8+ T细胞反应是否有助于损害了某些病毒株的清除。最后，来自供体的人外周血单核细胞携带与HASTV保护相关的MHC I类等位基因将用于识别免疫降级 HASTV CD8+ T细胞表位，允许四聚体的开发表征HASTV特异性CD8+ T细胞与这个共同等位基因的各种捐助者的表型。这些研究非常适合R21赠款机制，因为它们涉及开发关键使用尚未应用于ASTV的方法进行免疫研究的工具。完成此操作提案都将提供对针对ASTV的细胞免疫反应的关键见解，并发展四聚体自然感染和疫苗接种后，用于未来定义T细胞反应的试剂。更远，鉴定出的免疫主导表位将代表针对疫苗和细胞疗法的重要靶标这些临床上重要的肠病毒病原体。