Evolution of Cryptococcus neoformans Strains from Patients with HIV/AIDS

HIV/AIDS 患者的新型隐球菌菌株的进化

• 批准号: 9981611
• 负责人: John R. Perfect
• 金额: $ 34.76万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-08-05 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9981611
• 关键词: AIDS population; AIDS/HIV problem; Age; Animal Model; Animals; Antifungal Agents; Basic Science; Behavior; Bioinformatics; Biological Assay; Brain Diseases; Cell Size; Cell Wall; Cell membrane; Cells; Censuses; Central Nervous System Diseases; Central Nervous System Infections; Cessation of life; Clinical; Communities; Complex; Country; Cryptococcal Meningitis; Cryptococcosis; Cryptococcus; Cryptococcus neoformans; Data; Disease; Disease Outcome; Drug Targeting; Drug resistance; Encapsulated; Environment; Evolution; Explosion; Future; G Cells; Genes; Genetic; Genetic Crosses; Genetic Transcription; Genome; Genomics; Genotype; Goals; Growth; Health Care Costs; Healthcare Systems; High temperature of physical object; Human; Immune response; Immunocompromised Host; In Vitro; Infection; Infrastructure; Internet; Investigation; Knowledge; Libraries; Link; Lung diseases; Melanins; Meningitis; Metabolic; Molecular; Morbidity - disease rate; Movement; Mus; Oryctolagus cuniculus; Outcome; Partner in relationship; Pathogenesis; Pathogenicity; Pathway interactions; Patients; Phagocytosis; Phenotype; Phylogenetic Analysis; Plague; Population; Populations at Risk; Production; Recording of previous events; Research; Resources; Risk; Spottings; Structure of thyroid parafollicular cell; System; Treatment Protocols; Validation; Virulence; Virulent; Work; Yeasts; aggressive therapy; antiretroviral therapy; base; cell capsule; cost; design; fitness; fungus; genetic linkage; genetic pedigree; genome sciences; genome sequencing; genome wide association study; genomic data; genomic locus; health care availability; human data; human disease; human pathogen; insight; mortality; outcome forecast; pathogen; pathogenic fungus; phenotypic data; population genetic structure; public health relevance; response; robotic system; screening; stressor; sugar; tool; treatment strategy; whole genome

Abstract This competitive renewal will continue to work on understanding the population genetic structures of Cryptococcus neoformans. With this massive genome sequencing data, we will expand it and add a functional and/or translational focus. Importantly, the sequence data are integrated with phenotypic data, animal models and human infection outcomes to help understand the genetic components that make it a deadly human pathogen.Cryptococcus neoformans represents a group of encapsulated basidiomycetous yeasts that continue to produce hundreds of thousands of cases of meningitis each year with mortality rates of 15 to over 50% depending on the health care systems and no new antifungal agents have been discovered for its treatment in 25 years. In this proposal, we will use whole genome sequences to direct a research platform to complete two Specific Aims that are framed in questions. Specific Aim 1 is: What are the genotypic and phenotypic differences between clinical and environmental strains. Specific Aim 2 examines the following question: Within clinical isolates that have already produced disease, why are some strains more virulent or aggressive than others? The goal of this proposal is three- fold. First, to use whole genome sequencing (WGS) and GWAS in a large number of strains linked to functional data in order to dial down into wild-type strains and find specific genes and/or networks important to C. neoformans fitness/survival in the mammalian host. Thus, we will identify potential weak spots in the fungus to be used for antifungal drug targets. Second, to genetically identify “bad actor” strains producing more aggressive disease behaviors that could be identified for the treating clinician to appreciate and thus adjust treatment regimens based on this knowledge of the strain’s pathobiology. Finally, this study will create a substantial infrastructure addition of a library of well-characterized wild-type strains for use by the entire cryptococcal community for future pathobiology work.

抽象的 这种竞争性更新将继续致力于了解种群遗传结构 有了这些大量的新型隐球菌基因组测序数据，我们将对其进行扩展并添加功能。 重要的是，序列数据与表型数据、动物模型相整合。 和人类感染结果，以帮助了解使其成为致命人类的遗传成分 病原体。新型隐球菌代表一组包封的担子菌酵母，它们继续 每年产生数十万例脑膜炎病例，死亡率为 15% 至 50% 以上 取决于医疗保健系统，并且尚未发现新的抗真菌药物可用于治疗 在这个提案中，我们将利用全基因组序列来指导一个研究平台完成两项工作。 问题 1 中提出的具体目标是：基因型和表型是什么。 临床菌株和环境菌株之间的差异具体目标 2 检查以下内容。 问题：在已经产生疾病的临床分离株中，为什么有些菌株的致病力更强？ 该提案的目标有三个：首先，使用全基因组。 对大量菌株进行测序（WGS）和 GWAS 并与功能数据相关联，以便深入了解 野生型菌株并找到对新型隐球菌适应/生存重要的特定基因和/或网络 因此，我们将确定真菌中潜在的弱点，用于抗真菌药物。 其次，从基因上识别产生更具侵袭性疾病行为的“不良行为者”菌株。 可以确定治疗临床医生的理解，从而根据此调整治疗方案 最后，这项研究将创建一个实质性的基础设施补充。 特征明确的野生型菌株库，供整个隐球菌社区未来使用 病理生物学工作。