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.

摘要 这种竞争性的更新将继续致力于了解种群遗传结构， 新型隐球菌。有了这个庞大的基因组测序数据，我们将扩大它，并添加一个功能 和/或平移聚焦。重要的是，将序列数据与表型数据、动物模型 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， 新型隐球菌代表了一组被包裹的担子菌酵母， 每年产生数十万例脑膜炎病例，死亡率为15%至50%以上， 这取决于卫生保健系统，目前还没有发现新的抗真菌药物用于治疗， 25年在这个建议中，我们将使用全基因组序列来指导一个研究平台， 在问题中提出的具体目标。具体目标1是：什么是基因型和表型 临床和环境菌株之间的差异。具体目标2审查了以下内容 问题：在已经产生疾病的临床分离株中，为什么有些菌株更容易感染 比其他人更恶毒或更具攻击性？这项建议有三个目标。第一，使用全基因组 测序（WGS）和GWAS在大量的菌株链接到功能数据，以拨号到 野生型菌株，并找到特定的基因和/或网络重要的C.新形式的健身/生存在 哺乳动物宿主因此，我们将确定潜在的弱点，在真菌用于抗真菌药物 目标的第二，从基因上鉴定出产生更具侵略性疾病行为的"坏演员"菌株， 从而基于此调整治疗方案 了解菌株的病理学最后，这项研究将创造一个实质性的基础设施， 一个充分表征的野生型菌株库，供整个隐球菌社区将来使用 病理生物学工作。