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 球虫病（山谷热）是美国西南部和 所有访问那里的人。一小部分感染导致渐进，使人衰弱，甚至威胁生命 疾病（传播球菌病或DCM）。所有证据表明，这种增强的敏感性是 由于患者免疫反应的差异，在公开免疫缺陷中清楚地理解了 人（即有艾滋病的人），但对于绝大多数健康的患者而言， DCM。 NIAID壁内PI（Steven Holland博士）已确定了一些患者的遗传基因突变 每个都与DCM相关。他还发现其他DCM患者具有稀有基因 变体可能会产生有害后果。这些发现为途径提供了线索 在其他DCM患者中可能会放松管制，但没有容易识别的遗传 交替。该项目建立在荷兰博士和约翰·加尔吉亚尼博士之间的持续合作基础上 亚利桑那大学（UA）山谷热卓越中心主任，以维持转诊路径 居住在亚利桑那州的受试者参加NIH临床中心现有计划。这项工作将更好地定义 荷兰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核细胞的基因表达 与控制coccidioyal的人相比，DCM与Mendelian突变无关的患者 感染而不会生病。这种比较可能会识别反应的失调模式，并建议 在此类患者中，这种推动的有害变体可能是负责任的。第三个目标是基因 将与人类DCM相关的Mendelian突变（例如荷兰博士在STAT4中发现的）引入 小鼠菌株通常抗球菌传播，以确定这种突变是否导致 DCM增加。如果是这样，我们还可以发现是否有可能通过 免疫。鼠研究将使用UA可用的遏制设施，目前尚不可用 在NIH。由于这项工作，可能可以识别出那些会感染DCM的人。 此外，我们的发现可能建议使用新的治疗方法或预防疫苗。

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

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