Genetics of Cryptococcus sexual reproduction

隐球菌有性繁殖的遗传学

• 批准号: 8645574
• 负责人: JOSEPH HEITMAN
• 金额: $ 43.98万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-05-01 至 2016-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8645574
• 关键词: AIDS/HIV problem; Acquired Immunodeficiency Syndrome; Address; Africa; Aneuploidy; Animal Model; Attenuated; Award; Azoles; Beryllium; Biology; Brain; Breathing; Candida; Candida albicans; Carbon Dioxide; Cell Surface Receptors; Cessation of life; Chromosomal translocation; Clinical; Columbidae; Communicable Diseases; Coupled; Cryptococcus; Cryptococcus neoformans; DNA; DNA Transposable Elements; Darkness; Diploidy; Disease Outbreaks; Double-Stranded RNA; Drug resistance; Evolution; Exhibits; Fungal Drug Resistance; GTP-Binding Proteins; Gender Role; Generations; Genes; Genetic; Genetic Markers; Genetic Population Study; Genetic Variation; Genome; Genome Stability; Genomic Instability; Genomics; Genotype; Hereditary Disease; Human; Immunocompetent; Immunocompromised Host; Inbreeding; Individual; Infection; Inositol; Investigation; Life; Light; Link; Lung; Mating Types; Melanins; Meningitis; Mental Depression; Microbe; Mitochondria; Modeling; Molecular; Morbidity - disease rate; Mutation; Nature; Nuclear; Nutrient; Oregon; Pacific Northwest; Parasites; Partner in relationship; Pathway interactions; Patients; Phenotypic Sex; Pheromone Receptors; Plants; Ploidies; Pneumonia; Population; Population Genetics; Prevention; Process; Production; Proteins; RNA; RNA Interference; RNA Processing; RNA-Directed RNA Polymerase; Reporter; Reproduction; Reproduction spores; Role; Route; Shapes; Site; Source; Structure; Temperature; Testing; Transcript; Transgenes; Trees; Tuberculosis; United States; Virulence; Zinc Fingers; aerosolized; base; fungus; human DICER1 protein; insight; macrophage; microbial; mortality; mutant; novel; offspring; pathogen; public health relevance; research study; response; sex; tool; transcription factor

DESCRIPTION (provided by applicant): Cryptococcus neoformans and Cryptococcus gattii frequently infect humans to cause life-threatening pneumonia and meningitis resulting in considerable morbidity and mortality in both immunocompromised and immunocompetent hosts. More than one million cases of cryptococcal infection occur globally annually, resulting in >620,000 deaths and up to one-third of all AIDS-associated deaths. An outbreak of C. gattii in the Pacific Northwest involves non-AIDS patients, the majority of whom are immunocompetent, and our investigations document this outbreak has expanded into the US and novel hypervirulent genotypes have emerged. Both Cryptococcus species have a defined sexual cycle involving two opposite mating types (a,a). However, because the vast majority of clinical and environmental isolates are a mating type, it had been unclear if sex occurs in nature and how aerosolized spores thought to be infectious propagules arise. We discovered a novel sexual cycle involving only one mating type, termed a-a same-sex mating or unisexual reproduction. Our population genetic studies provide substantial evidence that unisexual reproduction is a predominant route generating genetic diversity in nature. Our studies further demonstrate that spores produced by sex are infectious following inhalation, and thus unisexual reproduction may be the source of human infections. Candida albicans was also recently discovered to undergo same-sex mating, and cryptic sexual cycles are being found for other fungal and parasite eukaryotic pathogens. Thus, our studies on the roles of sex in pathogen evolution and emergence are of general importance. Our studies supported by this award have defined conditions and genetic circuits governing a-a opposite and a-a unisexual reproduction of Cryptococcus. We have 1) shown that sex occurs in common environmental niches (pigeon guano, plants/trees) and in response to nutrient limitation, light/darkness, carbon dioxide, and inositol; 2) elucidated same-sex genetic cascades involving the novel cell surface receptor Cpr2 and the nuclear transcription factors Mat2 and Znf2; 3) adduced robust population genetic evidence that unisexual reproduction occurs in nature; and 4) shown that sexual reproduction has shaped the C. gattii population structure with implications for pathogen emergence. Our hypothesis is that a-a unisexual reproduction generates genetic diversity and infectious spores. Our recent studies reveal novel features of sexual reproduction allowing us to propose three new aims to test these hypotheses. Aim 1 is to elucidate how the RNAi-dependent sex-induced silencing pathway functions to guard genome integrity. Aim 2 focuses on the de novo generation of genotypic and phenotypic plasticity by sexual reproduction involving aneuploidy and diploidy. Aim 3 addresses sexual reproduction and the basis of hypervirulence in the C. gattii Pacific Northwest outbreak. These studies will advance understanding of how microbial pathogens evolve and emerge via sexual reproduction with implications for treatment and prevention.

描述（由申请人提供）：加密的新羊角和加蒂的隐孢子虫经常感染人类会导致危害生命的肺炎和脑膜炎，从而在免疫强化和不受限制的宿主中导致相当大的发病率和死亡率。每年全球有超过一百万个隐球菌感染病例，导致> 620,000例死亡，最多三分之一的艾滋病相关死亡。太平洋西北地区的C. gattii爆发涉及非AIDS患者，其中大多数具有免疫能力，我们的调查记录了这次爆发已扩展到美国，并且已经出现了新型的高毒性基因型。两种加密环球都有一个定义的性周期，涉及两种相反的交配类型（a，a）。但是，由于绝大多数临床和环境分离株都是一种交配类型，因此尚不清楚性别是否发生在自然界中，以及被认为是传染性繁殖体的气溶化孢子。我们发现了一个新的性周期，仅涉及一种交配类型，称为A-A同性交配或单性繁殖。我们的人群遗传研究提供了大量证据，表明中性繁殖是产生自然界遗传多样性的主要路线。我们的研究进一步表明，在吸入后，性别产生的孢子是感染性的，因此单性繁殖可能是人类感染的根源。最近还发现白色念珠菌进行了同性交配，并发现其他真菌和寄生虫真核病原体也发现了隐性的性周期。因此，我们对性别在病原体进化和出现中的作用的研究至关重要。 该奖项支持的我们的研究确定了管理A-A相反和A-A中的遗传回路的遗传回路。我们有1）表明，性别发生在常见环境壁ni（鸽子鸟粪，植物/树木）中，并响应营养限制，光/黑暗，二氧化碳和肌醇； 2）阐明了涉及新细胞表面受体CPR2和核转录因子Mat2和Znf2的同性遗传级联反应； 3）提出了强大的人口遗传证据，即在自然界中发生中性繁殖； 4）表明，性繁殖已塑造了C. gattii种群结构，对病原体的出现有影响。我们的假设是A-A单性繁殖产生了遗传多样性和传染性孢子。我们最近的研究揭示了有性繁殖的新特征，使我们提出了三个新的目标来检验这些假设。目的1是阐明RNAi依赖性性诱导的沉默途径如何捍卫基因组完整性。 AIM 2的重点是通过涉及非整倍性和二倍体的有性繁殖的基因型和表型可塑性的从头产生。 AIM 3解决了C. gattii Pacific Northwest爆发中的性繁殖和过度投资基础。这些研究将进一步了解微生物病原体如何通过有性繁殖以及对治疗和预防的影响而发展。