Evolution of Cryptococcus neoformans strains from patients with HIV/AIDS

来自艾滋病毒/艾滋病患者的新型隐球菌菌株的进化

• 批准号: 8511334
• 负责人: John R. Perfect
• 金额: $ 42.87万
• 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 2016-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8511334
• 关键词: AIDS/HIV problem; Africa; Africa South of the Sahara; African; Animal Disease Models; Antifungal Agents; Area; Biological Assay; Birds; Botswana; Breathing; Cells; Cessation of life; Clinical; Columbidae; Complex; Cryptococcus neoformans; Cryptococcus neoformans infection; Data; Disease; Environment; Environmental Risk Factor; Evolution; Feces; Frequencies; Fungal Drug Resistance; Genes; Genetic; Genetic Markers; Genetic Recombination; Genetic Variation; Genome; Genomics; Genotype; Habitats; High Prevalence; Human; In Vitro; Incidence; Indigenous; Infection; Laboratories; Link; Low Prevalence; Mammals; Maps; Medical; Melanins; Meningoencephalitis; Methods; Molecular; Morbidity - disease rate; Mus; Nature; Pathogenesis; Pathogenicity; Patients; Phylogenetic Analysis; Polysaccharides; Population; Population Genetics; Population Study; Prevalence; Probability; Proliferating; Public Health; Recording of previous events; Recovery; Research; Resources; Rock Pigeons; Sampling; Serotyping; Severities; South Africa; Southern Africa; Stress; Structure; Technology; Testing; The science of Mycology; Trees; Virulence; Virulence Factors; Yeasts; capsule; comparative; comparative genomics; density; fungus; genetic analysis; genetic evolution; genome sequencing; genome wide association study; human disease; innovation; macrophage; mortality; pathogen; pressure

DESCRIPTION (provided by applicant): Over a million patients with HIV/AIDS are currently afflicted with fungal meningoencephalitis, and the resultant morbidity and mortality are profoundly significant. The vast majority of these infections are caused by strains of Cryptococcus neoformans var. grubii, which have been recognized by possessing capsular serotype A. This yeast is ubiquitous in the environment, where it is associated with avian habitats and vegetative debris. Infection is not contagious but acquired exogenously by the inhalation of desiccated yeast cells or basidiospores. Although the ability to infect mammals offers no obvious evolutionary advantage to the fungus, most natural isolates are capable of colonizing mammalian hosts, which suggests that pathogenicity evolved in the environment. In preliminary studies, we developed robust multilocus genotyping methods and discovered two unique, genetically isolated subpopulations of serotype A: (i) a global subpopulation comprised of ubiquitous, highly clonal monomorphic strains associated with the excreta of feral pigeons and (ii) a unique, highly-variable, recombining subpopulation in southern Africa that is associated with indigenous African trees. The genetic diversity of this southern African population is unprecedented and suggests that this population may represent ancestral origin of the extant, global strains of serotype A. We also analyzed the frequencies of multilocus genotypes among clinical and environmental samples and discovered that not all strains (or genotypes) are equally likely to cause cryptococcal disease in humans. Despite the enormous diversity of genotypes in the African population, almost half of all patients in Botswana (46%) and a major proportion of patients in South Africa (17%) were infected by strains with three closely related genotypes. In contrast, the distribution of genotypes among environmental isolates in Africa is comparable, and none are dominant. Among global isolates, most genotypes were equally prevalent in both patients and the predominant non-African ecological niche, pigeon feces, although one genotype (A2) was highly prevalent in the environment but never isolated from patients. This proposal will investigate the evolution of pathogenicity in C. neoformans at the population genetic and genomic levels. This project involves two independent but complementary aims. Aim 1 will use methods of population genetic and phylogenetic analysis to test the hypothesis of the African origin of serotype A. Aim 2 will use methods of comparative genomics, genome-wide association mapping and phenotypic assays to identify genomic regions that differentiate strains that frequently cause infection from strains that are rarely, if ever, isolated from humans. This application of whole-genome methods to natural strains of C. neoformans will identify genes or genomic regions that are significantly associated with pathogenicity for humans.

描述（由申请人提供）：超过一百万的艾滋病毒/艾滋病患者目前患有真菌脑膜脑炎，由此产生的发病率和死亡率非常重要。这些感染中的绝大多数是由新虫的菌株菌株引起的。 Grubii，通过拥有囊血清型A来识别。该酵母在环境中无处不在，它与禽栖息地和营养碎屑有关。感染不是传染性的，而是通过吸入干燥的酵母细胞或大孢子的吸入而外源的。尽管感染哺乳动物的能力对真菌没有明显的进化优势，但大多数天然分离株都能定植哺乳动物宿主，这表明致病性在环境中进化。 In preliminary studies, we developed robust multilocus genotyping methods and discovered two unique, genetically isolated subpopulations of serotype A: (i) a global subpopulation comprised of ubiquitous, highly clonal monomorphic strains associated with the excreta of feral pigeons and (ii) a unique, highly-variable, recombining subpopulation in southern Africa that is associated with indigenous非洲树。该南部非洲人口的遗传多样性是前所未有的，这表明该人群可能代表了血清型A的现存全球菌株的祖先起源。我们还分析了临床和环境样本中多核基因型的频率，并发现并非所有菌株（或基因型）并非所有菌株都可能导致Cryptoccoccal病的菌株。尽管非洲人群的基因型多样性多样性，但博茨瓦纳的所有患者中，几乎一半（46％）和南非的大部分患者（17％）被三种密切相关的基因型的菌株感染。相反，非洲环境分离株之间基因型的分布是可比的，没有主导。在全球分离株中，大多数基因型在患者和主要的非非洲生态生态壁sikeon pigeon Feces中同样普遍，尽管一种基因型（A2）在环境中非常普遍，但从未与患者分离。 该建议将研究新生梭菌在种群遗传和基因组水平上致病性的演变。该项目涉及两个独立但互补的目标。 AIM 1将使用种群遗传和系统发育分析的方法来检验血清型A的非洲起源A的假设A AIM 2将使用比较基因组学，全基因组范围的关联映射和表型测定的方法来识别基因组区域，从而鉴定出菌株经常引起菌株的菌株，这些菌株频繁地受到菌株的感染，如果有任何菌株，那是很少与人类分离出来的菌株。将全基因组方法应用于新生梭菌的天然菌株中，将识别与人类致病性显着相关的基因或基因组区域。