An evolutionary population genomics approach to determine the genetic basis of virulence in the pathogenic fungus Cryptococcus neoformans

一种确定致病真菌新型隐球菌毒力遗传基础的进化群体基因组学方法

• 批准号: MR/K000373/1
• 负责人: Matthew Fisher
• 金额: $ 71.69万
• 依托单位: Imperial College London
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2012
• 资助国家: 英国
• 起止时间: 2012 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FK000373%2F1
• 关键词: evolutionary; population; genomics; approach; determine

Infectious fungi are causing an increasing burden of disease worldwide. The fungus Cryptococcus neoformans infects individuals with damaged immune systems, such as those suffering from HIV/AIDS, commonly resulting in meningitis. This pathogen has become one of the leading fungal causes of disease and death worldwide, causing a million infections per year and 15-20% of all AIDS-related deaths. Research has shown that the ability to successfully infect, and to cause disease (virulence), largely depends on the DNA sequence (genotype) of the infecting Cryptococcus strain, and that a specific lineage (known as VNI) has undergone an ecological transition from a tree-associated wood-decaying organism to a bird-associated human pathogen. We have dated the emergence of this pandemic lineage out of Africa to colonise the world within the last 5,000 years. There is now an opportunity to determine how this emergence occurred, by sequencing the genomes of many environmental strains of C. neoformans and comparing their genetic diversity to that found causing disease in HIV patients worldwide. Our study will characterise the the genomic diversity of infecting Cryptococcus strains from HIV patients in affected regions of sub-saharan Africa and Southeast Asia. The African patients are being enrolled in a newly-funded MRC trial on the efficacy of antifungal drugs against cryptococcosis. We will collect isolates of C. neoformans from their environmental reservoir, trees, across South East Asia (principally Thailand) and sub-Saharan Africa, and compare their genome sequences to those known to cause disease in human patients. This will allow us to identify the genomic regions that are associated with virulence in humans, and will date major evolutionary events in C. neoformans, including the shuffling of genes through sexual recombination, how many lineages emerged from Africa to colonise the world, and when this occurred. Importantly, we will profile our environmental versus clinical infectious isolates with respect to key virulence determinants including size and shedding of their capsule, their ability to invade and grow within human macrophage cells and their ability to kill the model insect species Galleria mellonella. For isolates that show significant differences in virulence, we will profile patterns of gene expression for isolates cultured under conditions that mimic infection. These results will provide novel insights into diverse virulence determinants, some of which may provide new therapeutic targets against this difficult to treat infection.

感染性真菌正在全球范围内造成越来越多的疾病负担。新型隐球菌感染免疫系统受损的人，如艾滋病毒/艾滋病患者，通常导致脑膜炎。这种病原体已成为全球疾病和死亡的主要真菌原因之一，每年造成100万例感染和15-20%的艾滋病相关死亡。研究表明，成功感染和引起疾病（毒力）的能力在很大程度上取决于感染隐球菌菌株的DNA序列（基因型），并且一个特定的谱系（称为VNI）已经经历了从树木相关的木材腐烂生物到鸟类相关的人类病原体的生态转变。我们已经确定了这种流行病谱系在过去5,000年内从非洲出现并殖民世界的时间。现在有机会确定这种出现是如何发生的，通过对许多环境中的C。并将他们的遗传多样性与全球艾滋病患者的遗传多样性进行比较。我们的研究将证实感染隐球菌菌株的基因组多样性，这些菌株来自撒哈拉以南非洲和东南亚受影响地区的HIV患者。这些非洲患者正在参加一项新资助的MRC试验，该试验旨在研究抗真菌药物对隐球菌病的疗效。我们将收集C.该研究从东南亚（主要是泰国）和撒哈拉以南非洲的环境水库树木中提取新形虫，并将其基因组序列与已知导致人类患者疾病的基因组序列进行比较。这将使我们能够确定与人类毒性相关的基因组区域，并将确定C.新人类，包括通过性重组的基因洗牌，有多少血统从非洲出现殖民世界，以及何时发生。重要的是，我们将分析我们的环境与临床感染性分离株的关键毒力决定因素，包括其胶囊的大小和脱落，它们在人类巨噬细胞内侵入和生长的能力以及它们杀死模式昆虫物种大蜡螟的能力。对于在毒力方面表现出显著差异的分离株，我们将分析在模拟感染的条件下培养的分离株的基因表达模式。这些结果将为不同的毒力决定因素提供新的见解，其中一些可能为这种难以治疗的感染提供新的治疗靶点。

项目成果

Transcriptional Heterogeneity of Cryptococcus gattii VGII Compared with Non-VGII Lineages Underpins Key Pathogenicity Pathways.

• DOI: 10.1128/msphere.00445-18
• 发表时间: 2018-10-24
• 期刊: mSphere
• 影响因子: 4.8
• 作者: Farrer RA;Ford CB;Rhodes J;Delorey T;May RC;Fisher MC;Cloutman-Green E;Balloux F;Cuomo CA
• 通讯作者: Cuomo CA

An infectious way to teach students about outbreaks.

• DOI: 10.1016/j.epidem.2017.12.002
• 发表时间: 2018-06
• 期刊: Epidemics
• 影响因子: 3.8
• 作者: Cremin Í;Watson O;Heffernan A;Imai N;Ahmed N;Bivegete S;Kimani T;Kyriacou D;Mahadevan P;Mustafa R;Pagoni P;Sophiea M;Whittaker C;Beacroft L;Riley S;Fisher MC
• 通讯作者: Fisher MC

Advances in Cryptococcus genomics: insights into the evolution of pathogenesis.

• DOI: 10.1590/0074-02760170473
• 发表时间: 2018
• 期刊: Memorias do Instituto Oswaldo Cruz
• 影响因子: 2.8
• 作者: Cuomo CA;Rhodes J;Desjardins CA
• 通讯作者: Desjardins CA

The need for environmental surveillance to understand the ecology, epidemiology and impact of Cryptococcus infection in Africa.

• DOI: 10.1093/femsec/fiab093
• 发表时间: 2021-07-07
• 期刊: FEMS microbiology ecology
• 影响因子: 4.2
• 作者: Edwards HM;Cogliati M;Kwenda G;Fisher MC
• 通讯作者: Fisher MC

Cryptococcus neoformans

• DOI: 10.32388/r5e8vu
• 发表时间: 2020-02
• 期刊: Definitions
• 作者: Antonie Van Leeuwen