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: 10424470
• 负责人: John R. Perfect
• 金额: $ 36.39万
• 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 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10424470
• 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; Prognosis; 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; 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努力了解 加密赛车。使用此庞大的基因组测序数据，我们将扩展并添加功能 和/或翻译重点。重要的是，序列数据与表型数据，动物模型集成 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。晶体新生群代表一组封装的碱性酵母菌，继续 每年生产数十万例脑膜炎病例，死亡率为15至50％以上 根据医疗保健系统的不同，没有发现新的抗真菌药物的治疗 25年。在此建议中，我们将使用整个基因组序列指导一个研究平台完成两个 在问题中构成的具体目的。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。特定的目标2考试以下 问题：在已经产生疾病的临床分离株中，为什么有些菌株更多 强大还是侵略性？该提案的目标是三倍。首先，使用整个基因组 在与功能数据相关的大量菌株中的测序（WGS）和GWAS，以便拨入 野生型菌株并找到对新生梭菌适应性/生存至关重要的特定基因和/或网络 哺乳动物主人。这，我们将确定真菌中潜在的弱点以用于抗真菌药物 目标。第二，从遗传上识别“不良行为者”菌株，产生更具侵略性的疾病行为 可以识别为治疗临床的欣赏并因此基于此调整治疗方案 了解菌株病理生物学。最后，这项研究将创造大量的基础设施 特征良好的野生型菌株库，可供整个加密秒社区使用 病理生物学工作。

项目成果

Comparison of Cryptococcus gattii/neoformans Species Complex to Related Genera (Papiliotrema and Naganishia) Reveal Variances in Virulence Associated Factors and Antifungal Susceptibility.

• DOI: 10.3389/fcimb.2021.642658
• 发表时间: 2021
• 期刊: Frontiers in cellular and infection microbiology
• 影响因子: 5.7
• 作者: Oliveira LSS;Pinto LM;de Medeiros MAP;Toffaletti DL;Tenor JL;Barros TF;Neves RP;Neto RGL;Milan EP;Padovan ACB;Rocha WPDS;Perfect JR;Chaves GM
• 通讯作者: Chaves GM

Copy number variation contributes to cryptic genetic variation in outbreak lineages of Cryptococcus gattii from the North American Pacific Northwest.

• DOI: 10.1186/s12864-016-3044-0
• 发表时间: 2016-09-02
• 期刊: BMC genomics
• 影响因子: 4.4
• 作者: Steenwyk JL;Soghigian JS;Perfect JR;Gibbons JG
• 通讯作者: Gibbons JG

Present and Future Therapy of Cryptococcus Infections.

• DOI: 10.3390/jof4030079
• 发表时间: 2018-07-03
• 期刊: Journal of fungi (Basel, Switzerland)
• 作者: Mourad A;Perfect JR
• 通讯作者: Perfect JR

The antifungal pipeline: a reality check.

• DOI: 10.1038/nrd.2017.46
• 发表时间: 2017-09
• 期刊: Nature reviews. Drug discovery
• 作者: Perfect JR

The virulence factor urease and its unexplored role in the metabolism of Cryptococcus neoformans.

毒力因子脲酶及其在新型隐球菌代谢中的未探索的作用。

• DOI: 10.1093/femsyr/foaa031
• 发表时间: 2020
• 期刊: FEMS yeast research
• 影响因子: 3.2
• 作者: Toplis,Barbra;Bosch,Caylin;Schwartz,IlanS;Kenyon,Chris;Boekhout,Teun;Perfect,JohnR;Botha,Alfred
• 通讯作者: Botha,Alfred