Genomic Research Capacity Building for Cryptococcosis Translational Studies

隐球菌病转化研究的基因组研究能力建设

• 批准号: 10053575
• 负责人: Joel Bazira
• 金额: $ 56.32万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-01 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10053575
• 关键词: AIDS-Related Opportunistic Infections; Acquired Immunodeficiency Syndrome; Acute; Adult; Affect; Africa; African; Alleles; Basic Science; Biological Assay; Biological Markers; Biology; Brain; CD4 Positive T Lymphocytes; Caring; Cause of Death; Cerebrospinal Fluid; Cessation of life; Chromosome Structures; Clinical; Clinical Research; Communicable Diseases; Complex; Cryptococcal Meningitis; Cryptococcosis; Cryptococcus; Development; Diagnostic; Diagnostic tests; Disease; Exhibits; Failure; Foundations; Funding; Genes; Genetic; Genetic Variation; Genomics; Genotype; Goals; Human; Immune; Immune response; Immunity; Immunologic Markers; Immunologics; Immunology; Impairment; Individual; Infection; Inflammatory; Infrastructure; Institutes; Interleukin-2; Laboratories; Mediating; Medical; Meningitis; Minnesota; Molecular; Morbidity - disease rate; Mycoses; Neurocognitive Deficit; Neurologic; Neurological outcome; Outcome; Patient Isolators; Patient-Focused Outcomes; Patients; Persons; Phenotype; Plasma; Process; Research; Research Personnel; Risk Factors; Science; Serum; Single Nucleotide Polymorphism; Technology; Th1 Cells; Translating; Translational Research; Tuberculosis; Uganda; United States National Institutes of Health; Universities; Variant; Virulence; chemokine; clinical infrastructure; clinical practice; clinical sequencing; cytokine; fungal genetics; genome wide association study; genomic biomarker; high risk; in silico; knowledge base; monocyte; mortality; mortality risk; mouse model; nervous system disorder; neutrophil; novel; polarized cell; programs; public health relevance; research study; response; routine care; trait; translational study; treatment strategy

Abstract Cryptococcal meningitis (CM) is among the leading causes of death in AIDS-related opportunistic infections and causes 15% of AIDS-related mortality globally. In Uganda, CM accounts for 60% of adult meningitis in hospitalized patients. Even with treatment, the current mortality rate for CM is 65%, with surviving patients often exhibiting neurological impairment. This poor survival is due to a complex interaction between 1) failure to control fungal replication and 2) deleterious host immune response. To reduce CM deaths, we must simultaneously mitigate Cryptococcus virulence while rebalancing detrimental host responses towards protective immunity. The long-term objective of our research team is to identify novel treatment strategies for CM that reduce morbidity and mortality associated with this devastating disease. Our University of Minnesota, Mbarara University of Science and Technology, and Makerere University research team has collaborated on CM clinical studies since 2009 – including three NIH-funded trials. While similar clinical infrastructures are now present throughout Africa, there is still limited ability to perform associated basic and translational research related to CM. Thus, we will continue to build the infrastructure, knowledge base, and human capacity among African investigators to perform basic research in genomics and immunology that is translatable to clinical practice. Our research group has made two key discoveries that influence patient mortality with CM: a) an immune signature associated with patient mortality, and b) that Cryptococcus genotype affects both patient mortality and immune response. Specifically, our preliminary genome-wide association studies (GWAS) identified 38 Cryptococcus genes associated with immune response and patient mortality in closely related Ugandan CM patient isolates. Thus, the scientific objective for this proposal is to define the impact of these Cryptococcus biomarkers on the immune response, and validate a subset of the biomarkers in a mouse model of cryptococcosis. Two specific aims will accomplish this goal. In the first aim, we will identify genomic differences and biomarkers in Cryptococcus isolates that influence patient mortality and neurocognitive deficits after CM that encompass the genetic diversity present in Uganda. We will then analyze associations between these genetic differences and patient immune responses in the second aim to define both fungal genetic and human immune biomarkers that can be used in clinical practice as the first step towards development of a diagnostic bioassay. Taken together, these translational studies will define the molecular processes underlying CM and translate this information (i.e. biomarkers) into novel clinical assays to identify high-risk individuals for acute mortality or neurological impairment who would benefit from tailored medical care.

摘要 隐球菌性脑膜炎(CM)是艾滋病相关机会性疾病的主要死亡原因之一 在全球与艾滋病相关的死亡中，有15%是由感染和致病造成的。在乌干达，CM占成年人的60% 住院患者中的脑膜炎。即使接受治疗，目前CM的死亡率仍为65%， 存活的患者通常表现出神经功能障碍。这种糟糕的存活率是由于一个复杂的 1)未能控制真菌复制和2)有害的宿主免疫反应之间的相互作用。至 减少CM死亡，我们必须在重新平衡的同时降低隐球菌的毒力 有害的宿主对保护性免疫的反应。我们研究团队的长期目标是 是确定治疗CM的新治疗策略，以降低与此相关的发病率和死亡率 毁灭性的疾病。我们的明尼苏达大学、姆巴拉拉科技大学和 Makerere大学的研究团队自2009年以来一直在CM临床研究上进行合作--包括三项 美国国立卫生研究院资助的试验。虽然现在非洲各地都有类似的临床基础设施，但仍有 执行与CM相关的基础和翻译研究的能力有限。因此，我们将 继续在非洲调查人员中建设基础设施、知识库和人力资源能力 进行可转化为临床实践的基因组学和免疫学基础研究。 我们的研究小组取得了两项影响CM患者死亡率的关键发现：a)和 与患者死亡率相关的免疫标志，以及b)隐球菌基因对两者都有影响 患者死亡率和免疫反应。具体地说，我们初步的全基因组关联研究 (GWAS)确定了38个与免疫反应和患者死亡率相关的隐球菌基因 密切相关的乌干达CM患者分离株。因此，这项提案的科学目标是界定 这些隐球菌生物标记物对免疫反应的影响，并验证 隐球菌病小鼠模型中的生物标志物。有两个具体目标可以实现这一目标。在第一个 目的：确定影响患者的隐球菌分离株的基因组差异和生物标志物。 包括乌干达目前的遗传多样性的CM后的死亡率和神经认知缺陷。 然后，我们将分析这些遗传差异与患者免疫反应之间的关系 第二个目标是定义可用于临床的真菌遗传和人类免疫生物标记物 实践是发展诊断性生物测定的第一步。这些加在一起， 翻译研究将定义CM背后的分子过程，并翻译这些信息 (即生物标志物)纳入新的临床分析，以识别急性死亡或死亡的高危个体 神经损伤，谁将受益于量身定制的医疗护理。