Genomic Research Capacity Building for Cryptococcosis Translational Studies

摘要 隐球菌性脑膜炎（CM）是艾滋病相关的机会性感染中死亡的主要原因之一。 艾滋病毒感染和艾滋病相关死亡的15%的原因在全球。在乌干达，CM占成年人的60%， 住院病人的脑膜炎。即使经过治疗，目前CM的死亡率为65%， 存活的患者通常表现出神经损伤。这种可怜的生存是由于一个复杂的 1）不能控制真菌复制和2）有害的宿主免疫应答之间的相互作用。到 减少CM死亡，我们必须同时减轻隐球菌毒力，同时重新平衡 对保护性免疫的有害宿主反应。我们研究团队的长期目标 确定CM的新治疗策略，以降低与此相关的发病率和死亡率， 毁灭性的疾病我们明尼苏达大学、姆巴拉拉科技大学、 自2009年以来，Makerere大学的研究团队一直在合作进行CM临床研究，其中包括三项 NIH资助的试验。虽然类似的临床基础设施现在在整个非洲都存在，但仍然存在 有限的能力进行相关的基础和转化研究有关CM。因此，我们将 继续在非洲调查人员中建立基础设施、知识库和人员能力 进行基因组学和免疫学的基础研究，并将其转化为临床实践。 我们的研究小组已经取得了两个影响CM患者死亡率的关键发现：a） 与患者死亡率相关免疫特征，和B）隐球菌基因型影响两者 患者死亡率和免疫反应。具体来说，我们初步的全基因组关联研究 （GWAS）鉴定了38个与免疫应答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，本提案的科学目标是确定 这些隐球菌生物标志物对免疫应答的影响，并验证了 隐球菌病小鼠模型中的生物标志物。两个具体目标将实现这一目标。上 目的是，我们将确定隐球菌分离株的基因组差异和生物标志物， CM后的死亡率和神经认知缺陷，包括乌干达存在的遗传多样性。 然后，我们将分析这些遗传差异与患者免疫反应之间的关联， 第二个目标是确定可用于临床真菌遗传和人类免疫生物标志物 实践作为发展诊断生物测定法的第一步。综上所述各项 翻译研究将定义CM的分子过程，并翻译这些信息 (i.e.生物标志物）用于新的临床测定，以鉴定急性死亡的高风险个体，或 神经系统损伤的人将受益于量身定制的医疗护理。

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.