Immuno-Genetic Basis for Human Disseminated Coccidioidomycosis

人类播散性球孢子菌病的免疫遗传学基础

基本信息

批准号：
9457306
负责人：
JOHN N GALGIANI
金额：
$ 55.37万
依托单位：
UNIVERSITY OF ARIZONA
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-03-21 至 2021-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9457306
关键词：
Acquired Immunodeficiency Syndrome Arizona Body part Categories Centers for Disease Control and Prevention (U.S.)Clinical Coccidioides Coccidioidomycosis Collaborations Communities Complex Containment Contracts DNA Sequence Alteration Defect Development Disease Gene Expression Gene Expression Profiling Gene Mutation Genetic Human Immune response Immunization Immunocompetent Immunologic Deficiency Syndromes Immunologics In Vitro Infection Inherited Institution Integration Host Factors Joints Laboratories Life Lung Messenger RNA Mouse Strains Mus Mutation Mycoses National Institute of Allergy and Infectious Disease Neuraxis Other Genetics Outcome Pathway interactions Patients Pattern Peripheral Blood Lymphocyte Peripheral Blood Mononuclear Cell Persons Pneumonia Predisposition Preventive vaccine Procedures Protocols documentation Public Health Reporting Research Personnel Resistance Resources Risk STAT4 gene Severities Skin Southwestern United States Specimen Study models Syndrome Testing Time Tissues United States United States National Institutes of Health Universities Vaccination Variant Virulence Visit Work accurate diagnosis adaptive immunity biosafety level 3 facility bone desert fever experience genetic variant in vivo medical attention monocyte mouse model novel strategies pathogen patient response prevent programs response screening

项目摘要

Project Summary Coccidioidomycosis (Valley Fever) is a serious public health problem for the Southwestern United States and all who visit there. A small proportion of infections result in progressive, debilitating, even life-threatening illness (disseminated coccidioidomycosis or DCM). All evidence suggests that this heightened susceptibility is due to differences in immunologic responses of the patient, clearly understood in overtly immunodeficient persons (i.e., those with AIDS) but not understood for the large majority of otherwise healthy patients with DCM. The NIAID intramural PI (Dr. Steven Holland) has identified inheritable gene mutations in a few patients each of which are associated with DCM. He has also found additional patients with DCM to have rare gene variants possibly producing deleterious consequences. These discoveries provide clues to the pathways that might be deregulated in other patients with DCM but who do not have such readily identifiable genetic alternations. This project builds on the ongoing collaboration between Dr. Holland and Dr. John Galgiani, University of Arizona (UA) Director of the Valley Fever Center for Excellence, to maintain a referral path for subjects living in Arizona to the existing program at the NIH Clinical Center. This work will better define the functional consequences of the Mendelian mutations that Dr. Holland has identified and how those differences permit DCM to occur. A second aim is to analyze gene expression of peripheral blood mononuclear cells of patients with DCM not associated with Mendelian mutations in comparison to persons who control coccidioidal infection without becoming ill. Such comparisons may identify dysregulated patterns of response and suggest which putatively deleterious variants in such patients might be responsible. A third aim is to genetically introduce Mendelian mutations associated with human DCM (such as one found by Dr. Holland in STAT4) into a mouse strain normally resistant to coccidioidal dissemination to determine if such mutations result in increased DCM. If so, we can also discover whether it is possible to prevent DCM in the transfected mice by immunization. The murine studies will use containment facilities available at the UA and not currently available at the NIH. As a result of this work, it may be possible to identify persons who, if infected, will develop DCM. Also, our findings may suggest new approaches to therapy or preventative vaccines.

项目概要球孢子菌病（谷热）是美国西南部的一个严重的公共卫生问题所有访问那里的人。一小部分感染会导致病情进展、衰弱甚至危及生命疾病（播散性球孢子菌病或 DCM）。所有证据都表明，这种高度的易感性是由于患者免疫反应的差异，在明显的免疫缺陷中可以清楚地理解人（即患有艾滋病的人），但不了解大多数其他方面健康的患者 DCM。 NIAID 壁内 PI（Steven Holland 博士）在一些患者中发现了可遗传的基因突变其中每一个都与 DCM 相关。他还发现其他 DCM 患者具有罕见基因可能产生有害后果的变异。这些发现为研究途径提供了线索对于其他 DCM 患者，但他们没有如此容易识别的遗传基因，可能会放松管制。交替。该项目建立在 Holland 博士和 John Galgiani 博士之间持续合作的基础上，亚利桑那大学 (UA) 山谷热卓越中心主任，负责维持推荐路径居住在亚利桑那州的受试者参加 NIH 临床中心的现有计划。这项工作将更好地定义霍兰德博士确定的孟德尔突变的功能后果以及这些差异如何允许 DCM 发生。第二个目的是分析外周血单个核细胞的基因表达与控制球孢子菌的患者相比，患有与孟德尔突变无关的 DCM 患者感染而不生病。这种比较可以识别失调的反应模式并表明这些患者中被认为有害的变异可能是造成这种情况的原因。第三个目标是从基因角度将与人类 DCM 相关的孟德尔突变（例如 Holland 博士在 STAT4 中发现的突变）引入通常对球孢子传播具有抵抗力的小鼠品系，以确定此类突变是否会导致增加 DCM。如果是这样，我们还可以发现是否可以通过以下方法预防转染小鼠的 DCM：免疫接种。小鼠研究将使用 UA 现有但目前尚未提供的收容设施在美国国立卫生研究院。这项工作的结果是，有可能识别出感染后会发展为 DCM 的人。此外，我们的研究结果可能会提出新的治疗方法或预防性疫苗。