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HLA Alleles and the Progression of Human Cryptococcosis

HLA 等位基因与人类隐球菌病的进展

基本信息

批准号：
10192647
负责人：
Kirsten Nielsen
金额：
$ 19.3万
依托单位：
UNIVERSITY OF MINNESOTA
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：
2020-06-15 至 2024-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10192647
关键词：
AIDS/HIV problem Acquired Immunodeficiency Syndrome Alleles Area Attenuated Basic Science Biological Assay Brain CD4 Positive T Lymphocytes Cell Count Cells Cerebrospinal Fluid Cessation of life Characteristics Clinical Clinical Sciences Communicable Diseases Cryptococcal Meningitis Cryptococcosis Cryptococcus Cryptococcus neoformans Data Development Disease Disease Progression Foundations Functional disorder Future GTP-Binding Protein alpha Subunits, Gs Gene Frequency General Population Genes Genetic HIV HIV Infections HLA Antigens Health system Helper-Inducer T-Lymphocyte Histocompatibility Antigens Class II Human Immune Immune response Immune system Immunity Immunocompromised Host Immunologics Immunology Immunophenotyping Impairment Individual Infection Interferon Type II Knowledge Lung Maintenance Major Histocompatibility Complex Mediating Meningitis Methods Modality Mus Mycoses Neurologic Outcome Participant Pathway interactions Peptides Persons Population Prevalence Progressive Disease Proteins Research Risk Role Study models System T cell response T-Lymphocyte Technology Testing Th2 Cells Therapeutic Uganda Viral Load result Yeasts base cell mediated immune response cohort cytokine disorder control disorder risk healthy volunteer improved innovation interest knowledge base pathogenic fungus personalized medicine polarized cell response study population vaccine development

项目摘要

Project Summary Cryptococcus continues to cause significant disease in immunocompromised individuals, particularly those with HIV/AIDS. Understanding the interplay between the human immune system and this pathogenic fungus is critical if we hope to improve clinical outcomes. The overall scientific objective of the research is to understand how the immune system in humans is directed towards a protective or deleterious response in Cryptococcus infection, while the specific objective of this proposal is to determine factors that impact the helper T cell response in humans during cryptococcal meningitis. Notably, there is particular interest in how the HLA/MHC system influences CD4+ T cells in their response to Cryptococcus. To accomplish this, the first aim is to identify the most prevalent HLA alleles in persons with cryptococcal disease. The hypothesis is that certain HLA alleles are associated with developing progressive disease, while others are associated with attenuating or protecting against disease. Establishing HLA-disease associations not only carries important clinical and therapeutic implications, but creates the knowledge base for further immunological studies. Aim two will use immunophenotyping modalities to determine helper T cell responses in the cryptococcal- specific immune response. The use of CD4+ T cell tetramers on cells from HIV-infected humans provides a proof-of-concept model for the study of infectious disease-specific T cell responses going forward. Additionally, performing activation induced marker (AIM) assays on the same cohort will provide a comparator method in the testing of the hypothesis that Th1 helper T responses are more protective in cryptococcosis than Th2 responses. The data generated by this study will drive innovation in the areas of vaccine development, personalized medicine, and health systems implementation. By establishing the necessary data on HLA prevalence of our study population and successfully implementing our proposed immunology methods to determine disease-specific T cell responses, we will lay the foundation for future clinical and basic science studies to understand how the human immune system responds to infection with Cryptococcus and manipulate that response to reduce disease.

项目摘要隐球菌继续在免疫功能受损的人中引起重大疾病，特别是那些感染艾滋病毒/艾滋病的人。了解人类免疫系统与此之间的相互作用如果我们希望改善临床结果，病原真菌是至关重要的。总的科学目标是这项研究是为了了解人类的免疫系统是如何针对一种保护性或对隐球菌感染的有害反应，而这项提议的具体目标是确定在隐球菌性脑膜炎期间影响人类辅助T细胞反应的因素。值得注意的是，人们特别感兴趣的是，人类白细胞抗原/巨噬细胞集落刺激因子系统如何影响体内的CD4+T细胞。对隐球菌的反应。要做到这一点，第一个目标是确定最普遍的人类白细胞抗原隐球菌病患者的等位基因。假设某些人类白细胞抗原等位基因是与发展为进展性疾病有关，而另一些则与衰弱或预防疾病。建立人类白细胞抗原疾病关联不仅具有重要的临床意义和治疗意义，但为进一步的免疫学研究创造了知识基础。目标其中两个将使用免疫表型方法来确定隐球菌中的辅助T细胞反应- 特异性免疫反应。CD4+T细胞四聚体在HIV感染者细胞上的应用为传染病特异性T细胞反应的研究提供了概念验证模型往前走。此外，在同一队列上执行激活诱导标记(AIM)分析将提供了一种检验Th1辅助T反应更多的假设的比较器方法对隐球菌病的保护作用优于Th2反应。这项研究产生的数据将推动疫苗开发、个性化医疗和卫生系统领域的创新实施。通过建立我们研究人群中人类白细胞抗原流行率的必要数据成功实施我们提出的免疫学方法来确定疾病特异性T细胞我们将为未来的临床和基础科学研究奠定基础，以了解人类免疫系统对感染隐球菌做出反应，并操纵这种反应减少疾病。