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.

抽象的 隐球菌病是由隐球菌属的担子菌酵母引起的，代表了一种亚 巨大的全球健康负担。新型隐球菌是最常见的传染原，无处不在 存在于环境中，大多数人很可能接触到多种遗传因素 以及整个一生中表型多样化的隐球菌菌株。尽管如此，人类 历史上，隐球菌病的研究假设大多数感染是 由单一致病菌株引起。因此，人们对其发病率和患病率知之甚少。 多菌株或混合物种隐球菌感染或其临床影响。 在对杜克大学医院系统患者样本的初步研究中，我们发现 发现了数量惊人的混合隐球菌感染。我们现在建议特征 确定混合隐球菌的群体基因组结构和流行病学相关性 感染，使用一组从美国东南部收集的 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，并将这些数据与群体基因组和系统发育相结合 对同一地理区域的环境隔离物进行网络分析，以了解环境 混合感染的环境起源。有关频率和人口结构的信息 混合感染的发生率将与患者人口统计数据的流行病学分析相关 健康结果，了解谁可能感染混合隐球菌感染以及哪些感染 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是抗真菌药物的敏感性及其相互作用 宿主免疫系统。