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.

摘要

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.

加密环球感染的当前和未来疗法。

• 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 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

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