Immuno-Genetic Basis for Human Disseminated Coccidioidomycosis

项目摘要 球孢子菌病（山谷热）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进行性的、使人衰弱的、甚至危及生命的 疾病（播散性球孢子菌病或DCM）。所有证据都表明，这种高度敏感性是 由于患者免疫应答的差异，在明显免疫缺陷的患者中清楚地了解到， 人（即，艾滋病患者），但对于大多数其他方面健康的患者来说， DCM。NIAID内部PI（Steven Holland博士）已经在少数患者中发现了可遗传的基因突变 每个都与DCM相关。他还发现了其他患有DCM的患者具有罕见的基因， 可能产生有害后果的变体。这些发现提供了线索， 在其他DCM患者中可能失调，但这些患者没有这种容易识别的遗传基因， 交替该项目建立在荷兰博士和约翰·加尔贾尼博士正在进行的合作基础上， 亚利桑那大学（UA）卓越谷热中心主任，以保持转介路径， 生活在亚利桑那州的受试者在NIH临床中心的现有计划。这项工作将更好地定义 霍兰德博士发现的孟德尔突变的功能后果，以及这些差异是如何产生的。 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， 与控制球孢子虫感染的人相比，与孟德尔突变无关的DCM患者 感染而不生病。这样的比较可以识别失调的反应模式，并建议 这类患者中的哪些有害变异可能是罪魁祸首。第三个目标是从基因上 将与人DCM相关的孟德尔突变（例如Holland博士在STAT 4中发现的突变）引入 通常对球孢子菌传播具有抗性的小鼠品系，以确定此类突变是否导致 增加DCM。如果是这样的话，我们还可以发现是否有可能在转染小鼠中预防DCM， 次免疫鼠类研究将使用美国大学现有的、目前还没有的遏制设施。 在国家卫生研究院作为这项工作的结果，它可能会确定谁的人，如果感染，将发展扩张型心肌病。 此外，我们的研究结果可能为治疗或预防性疫苗提供新的方法。

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.