Population Structure and Clinical Impact of Multi-strain and Mixed-species Cryptococcal Infections

多菌株和混合物种隐球菌感染的人群结构和临床影响

• 批准号: 10724704
• 负责人: Paul Mitaari Magwene
• 金额: $ 24.15万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-06-06 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10724704
• 关键词: Acquired Immunodeficiency Syndrome; Acute; Antifungal Agents; Autoimmune Diseases; Basidiomycota; Cessation of life; Characteristics; Chronic; Clinical; Complex; Cryptococcal Meningitis; Cryptococcosis; Cryptococcus; Cryptococcus neoformans; Data; Disease; Environment; Epidemiology; Exposure to; Frequencies; Genetic; Genetic Structures; Genome; Genomics; Genotype; Geographic Locations; Geography; Goals; HIV Seropositivity; HIV/AIDS; Health; Health system; Heterogeneity; Human; Immune system; Immunocompetent; Immunocompromised Host; Incidence; Infection; Infectious Agent; Life; Link; Macrophage; Mycoses; Organ Transplantation; Outcome; Pathogenicity; Patient-Focused Outcomes; Patients; Persons; Phenotype; Phylogenetic Analysis; Population; Prevalence; Public Health; Research; Sampling; Solid; Southeastern United States; Standard Model; Structure; Study models; Time; Travel; Universities; University Hospitals; Virulence; Yeasts; chronic infection; clinical decision-making; co-infection; demographics; detection platform; drug sensitivity; exposed human population; genome sequencing; genomic variation; global health; mortality; pathogenic fungus; patient population

Abstract Cryptococcal disease, caused by basidiomycete yeasts of the genus Cryptococcus, represents a sub- stantial global health burden. Cryptococcus neoformans, the most common infectious agent, is ubiq- uitous in the environment and it is likely that most people are exposed to multiple genetically and phenotypically diverse Cryptococcus strains throughout their lifetimes. Despite this, human cryptococcosis has historically been studied under the assumption that a majority of infections are caused by single pathogenic strains. As a result, little is known about the incidence and prevalence of multi-strain or mixed-species cryptococcal infections or their clinical impact. In a preliminary study of patient samples from the Duke University Hospital System we de- tected a surprisingly high number of mixed Cryptococcus infections. We now propose to charac- terize the population genomic structure and epidemiological correlates of mixed Cryptococcus in- fections, using a set of more than 500 patient samples from the southeastern US collected over the last 30 years. We will analyze phenotypic and genomic heterogeneity within these patient samples to identify mixed infections, and combine these data with with population genomic and phyloge- netic analyses of environmental isolates from the same geographic region to understand the en- vironmental origins of mixed infections. Information on the frequency and population structure of mixed infections will be correlated with epidemiological analyses of patient demographics and health outcomes to understand who is likely to get mixed Cryptococcus infections and what such infections mean for health outcomes. We will also explore the impact of phenotypic heterogeneity, a key characteristic of mixed infections, on sensitivity to antifungal drugs and interactions with the host immune system.

摘要 隐球菌病，由隐球菌属的担子菌酵母引起，代表了一种亚 全球健康负担。新型隐球菌是最常见的感染因子，是ubiq- 在环境中是普遍存在的，而且很可能大多数人都暴露在多种遗传因素中。 和表型多样的隐球菌菌株。尽管如此，人类 隐球菌病历来是在假设大多数感染是 由单一致病菌株引起。因此，对该疾病的发病率和患病率知之甚少。 多菌株或混合种隐球菌感染或其临床影响。 在对来自杜克大学医院系统的患者样本的初步研究中，我们 发现了数量惊人的混合隐球菌感染我们现在建议查拉克- 研究了我国混合隐球菌的种群基因组结构和流行病学相关性， 感染，使用了一组来自美国东南部的500多名患者样本， 过去30年我们将分析这些患者样本中的表型和基因组异质性 识别混合感染，并将这些数据与人口基因组和遗传学相结合， 对来自同一地理区域的环境分离株进行遗传学分析，以了解该菌株的遗传学特征。 混合感染的病因。关于发生频率和人口结构的资料 混合感染的发生率将与患者人口统计学的流行病学分析相关， 健康结果，以了解谁有可能得到混合隐球菌感染， 感染意味着健康结果。我们还将探讨表型异质性的影响， 混合感染的一个关键特征，对抗真菌药物的敏感性和与 宿主的免疫系统