The Evolution and Genetics of Fungal Virulence

真菌毒力的进化和遗传学

• 批准号: 10796489
• 负责人: Helen Anne Murphy
• 金额: $ 41.55万
• 依托单位: COLLEGE OF WILLIAM AND MARY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-08 至 2026-09-07
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10796489
• 关键词: Accidents; Amoeba genus; Animals; Attention; Award; Cellularity; Chromosome Mapping; Clinical; Coculture Techniques; Collection; Communicable Diseases; Complex; Data; Dictyostelium discoideum; Disease; Environment; Equilibrium; Evolution; Genetic; Genome; Geography; Goals; Growth; Heterozygote; Immune system; Invertebrates; Knowledge; Larva; Lead; Life Cycle Stages; Link; Literature; Maps; Microbe; Microbial Biofilms; Modeling; Moths; Organism; Outcome; Pathogenesis; Pathogenicity; Phagocytes; Phagocytosis; Phenotype; Population; Predatory Behavior; Production; Reporting; Reproduction; Research; Resistance; Resources; Role; Saccharomyces cerevisiae; Saccharomycetales; Shapes; Surface; Surveys; Techniques; Temperature; Testing; Toxin; Variant; Virulence; Virulent; Waxes; World Health Organization; Yeast Model System; Yeasts; capsule; experimental study; fungal genetics; fungus; genetic variant; genome wide association study; high throughput screening; microbial; model organism; opportunistic pathogen; pathogen; pathogenic bacteria; pathogenic fungus; pathogenic microbe; preference; pressure; social; trait; undergraduate research

PROJECT SUMMARY The study of infectious disease often focuses on pathogenic microbes that either specialize on exploiting animal hosts or on commensals that switch to pathogenesis when the delicate balance between host and microbe is perturbed. These microbes are presumed to have co-evolved complex adaptations that allow survival and reproduction in and on hosts. However, there exists a broad range of microbial organisms that live in the open environment that are capable of causing disease when the opportunity arises. Such microbes also have adaptations that allow host exploitation, but the origin of these adaptations is unclear, as growth and survival in a host is not a required part of the lifecycle. The existence of virulence traits in environmentally- derived, opportunistic pathogens is likely due to selection favoring the traits for other uses in the non-host environment. This hypothesis is known as “coincidental selection” in the bacterial literature, and “accidental virulence” in the fungal literature. The threat of emerging bacterial pathogens has received far more attention than the threat of fungal pathogens. In 2022, the World Health Organization issued its first-ever report prioritizing fungal pathogens; three of the top four were environmental fungi. Thus, understanding the evolution of opportunistic pathogens is essential. Examples of ‘dual-use’ traits that are “accidentally selected” include multicellularity (e.g., biofilm formation, filamentous growth, aggregation), protective capsules, and toxin production. Selection for these traits can be imposed by the abiotic environment (e.g., temperature), but also by the biotic environment. Indeed, amoeba predation has been hypothesized to be a major selective force favoring dual-use traits and preadapting microbes to be resistant to phagocytes in the immune system. The research proposed here will use three biomedical models to investigate the relationship between dual-use traits, resistance to amoeba predation, and virulence. In Aim 1, a collection of 1000 isolates of the opportunistic budding yeast, Saccharomyces cerevisiae, will be investigated for the distribution and genetic basis of multicellular traits. To estimate predation resistance, the strains will also be subject to phagocytosis by the amoeba, Dictyostelium discoideum, and a subset will be tested for virulence against the invertebrate model host, larvae of the wax moth, Galleria mellonella. Aims 2 and 3 will focus on specific clinical yeast isolates. First, the genetic basis of the three traits will be explored with a mapping panel to determine whether there are overlapping variants among the traits. Then, to directly test the role of amoeba predation on fungal virulence, the yeast and amoeba will be co-cultured and co-evolved to determine whether predation selects for increased virulence. This research represents one of the largest phenotypic screens of dual-use and predation-resistance related traits in an opportunistic fungal species, and will generate experimental techniques that may be used in other fungal species.

项目摘要 传染病的研究通常集中在病原微生物上， 当宿主和动物之间的微妙平衡时， 微生物受到干扰。这些微生物被认为具有共同进化的复杂适应性， 在宿主体内和宿主上的生存和繁殖。然而，存在广泛的微生物有机体， 在开放的环境中，当机会出现时，它们能够引起疾病。这些微生物还 有适应性，允许主机剥削，但这些适应性的起源尚不清楚，作为增长和 在宿主中的存活不是生命周期的必需部分。环境中存在的毒力性状- 衍生的机会致病菌可能是由于选择有利于在非宿主中用于其他用途的性状 环境这种假说在细菌文献中被称为“巧合选择”，而在细菌中被称为“偶然选择”。 在真菌文献中的“毒力”。新兴细菌病原体的威胁受到了更多的关注 真菌病原体的威胁更大2022年，世界卫生组织发布了有史以来第一份报告， 优先考虑真菌病原体;前四名中有三名是环境真菌。因此，理解进化 机会性病原体是必不可少的。被“意外选择”的“两用”特征的例子包括 多细胞性（例如，生物膜形成、丝状生长、聚集）、保护性胶囊和毒素 生产对这些性状的选择可以由非生物环境（例如，温度），而且 生物环境的影响。事实上，变形虫的捕食被假设为一种主要的选择力 有利于双重用途特性和预适应微生物以抵抗免疫系统中的吞噬细胞。的 这里提出的研究将使用三种生物医学模型来调查双重用途之间的关系 性状、对变形虫捕食的抗性和毒力。在目标1中，收集了1000株机会性大肠杆菌， 芽殖酵母，酿酒酵母，将调查的分布和遗传基础， 多细胞性状为了评估捕食抗性，菌株还将受到噬菌体的吞噬作用。 将检测阿米巴、盘基网柄线虫和一个子集对无脊椎动物模型的毒力 寄主是蜡螟的幼虫大蜡螟目标2和3将集中于特定的临床酵母菌分离株。 首先，这三个性状的遗传基础将通过作图小组进行探索，以确定是否存在 特征之间的重叠变体。然后，为了直接测试阿米巴捕食对真菌毒力的作用， 酵母和变形虫将共同培养和共同进化，以确定捕食是否选择增加 毒性这项研究代表了一个最大的表型筛选两用和捕食抗性 相关性状的机会真菌物种，并将产生实验技术，可用于 其他真菌物种。