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

• 批准号: 9884535
• 负责人: JOHN N GALGIANI
• 金额: $ 56.35万
• 依托单位: UNIVERSITY OF ARIZONA
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-03-21 至 2022-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9884535
• 关键词: Acquired Immunodeficiency Syndrome; Arizona; Body part; Category C pathogen; Centers for Disease Control and Prevention (U.S.); 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; clinical center; desert fever; experience; genetic variant; in vivo; medical attention; monocyte; mouse model; novel strategies; patient response; prevent; programs; response; screening

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.

项目摘要 球孢子菌病(山谷热)是美国西南部的严重公共卫生问题， 所有去过那里的人。一小部分感染会导致进展，使人虚弱，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，这种高度易感性是 由于患者的免疫反应不同，明确理解为明显免疫缺陷 人(即，艾滋病患者)，但对绝大多数原本健康的患者 DCM。NIAID内壁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相关联。他还发现了更多的扩张型心肌炎患者具有罕见的基因 可能产生有害后果的变种。这些发现提供了线索，表明 可能在其他扩张型心肌病患者中解除调控，但这些患者没有这种容易识别的基因 有变化的。这个项目建立在霍兰德博士和约翰·加尔吉亚尼博士之间正在进行的合作之上， 亚利桑那大学(UA)硅谷发烧卓越中心主任，为 居住在亚利桑那州的受试者参加NIH临床中心现有的计划。这项工作将更好地定义 霍兰德博士已经确定的孟德尔突变的功能后果以及这些差异是如何 允许发生DCM。第二个目的是分析老年人外周血单个核细胞的基因表达。 与控制球虫的患者相比，扩张型心肌病患者与孟德尔突变无关 感染而不生病。这样的比较可能会识别出失调的反应模式，并提示 这类患者中可能存在哪些有害的变异基因。第三个目标是从基因上 将与人类DCM相关的孟德尔突变(如Holland博士在STAT4中发现的一种)引入 一种通常抵抗球虫传播的小鼠品系，以确定这种突变是否会导致 增加了DCM。如果是这样的话，我们还可以发现是否有可能通过以下方式预防转基因小鼠的DCM 免疫接种。小鼠研究将使用UA现有的遏制设施，但目前还没有 在国立卫生研究院。这项工作的结果是，有可能确定如果被感染，将发展为扩张型心肌炎的人。 此外，我们的发现可能会为治疗或预防性疫苗提供新的方法。

项目成果

Personalized beyond Precision: Designing Unbiased Gold Standards to Improve Single-Subject Studies of Personal Genome Dynamics from Gene Products.

• DOI: 10.3390/jpm11010024
• 发表时间: 2020-12-31
• 期刊: Journal of personalized medicine
• 作者: Rachid Zaim S;Kenost C;Zhang HH;Lussier YA
• 通讯作者: Lussier YA

Mouse Model of a Human STAT4 Point Mutation That Predisposes to Disseminated Coccidiomycosis.

• DOI: 10.4049/immunohorizons.2200007
• 发表时间: 2022-02-11
• 期刊: ImmunoHorizons
• 作者: Powell, Daniel A;Hsu, Amy P;Shubitz, Lisa F;Butkiewicz, Christine D;Moale, Hilary;Trinh, Hien T;Doetschman, Thomas;Georgieva, Teodora G;Reinartz, Dakota M;Wilson, Justin E;Orbach, Marc J;Holland, Steven M;Galgiani, John N;Frelinger, Jeffrey A
• 通讯作者: Frelinger, Jeffrey A

Interpretation of 'Omics dynamics in a single subject using local estimates of dispersion between two transcriptomes

• 发表时间: 2019
• 期刊: AMIA ... Annual Symposium proceedings. AMIA Symposium
• 作者: Qike Li;Samir Rachid Zaim;Dillon Aberasturi;J. Berghout;Haiquan Li;Francesca Vitali;C. Kenost;H. Zhang;Y. Lussier

Exploring Wound-Healing Genomic Machinery with a Network-Based Approach.

• DOI: 10.3390/ph10020055
• 发表时间: 2017-06-21
• 期刊: Pharmaceuticals (Basel, Switzerland)
• 作者: Vitali F;Marini S;Balli M;Grosemans H;Sampaolesi M;Lussier YA;Cusella De Angelis MG;Bellazzi R
• 通讯作者: Bellazzi R