Examining the role of opportunistic human pathogen Aspergillus flavus in fungal keratitis eye infections

检查机会性人类病原体黄曲霉在真菌性角膜炎眼部感染中的作用

• 批准号: 10693803
• 负责人: Elizabeth Anne Hatmaker
• 金额: $ 3.18万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10693803
• 关键词: Affect; Anabolism; Annual Reports; Antifungal Agents; Aspergillosis; Aspergillus; Aspergillus flavus; Attenuated; Biological; Biology; Blindness; Case Study; Chemicals; Clinical; Contact Lenses; Cornea; Corneal Ulcer; Data; Developed Countries; Developing Countries; Disease; Disease model; Drug Tolerance; Eye; Eye Infections; Fermentation; Fungal Genome; Gene Cluster; Genes; Genetic; Genetic Determinism; Genetic Variation; Genome; Genomics; Goals; Growth; High temperature of physical object; Human; Human body; Industrialization; Infection; Infectious Agent; Invertebrates; Keratitis; Keratoplasty; Knowledge; Metabolic; Metabolism; Molds; Mycoses; Mycotoxins; Pathogenicity; Pathology; Phenotype; Physiological; Plants; Population; Production; Reproduction spores; Respiratory Tract Infections; Risk Factors; Role; Structure; Surface; Taxonomy; Temperature; Testing; Tissues; Variant; Virulence; candidate identification; comparative; experimental study; fungus; genetic element; genetic variant; genomic variation; human pathogen; insight; pathogen; response; secondary metabolite; stem; trait; wound

Project Summary Aspergillus species are a leading cause of fungal infections in humans as the disease agents for both aspergillosis respiratory infections and fungal keratitis (FK) eye infections. FK can necessitate a corneal transplant or have the devastating consequence of blindness. Over a million new cases of FK are reported annually worldwide. The primary risk factors for FK are contact lens use and surface scratches on the eye, which allow infection of the cornea; damage occurs as the fungus grows into the cornea. The filamentous fungus Aspergillus flavus is a leading cause of FK infections and is isolated from FK corneal ulcers more frequently than any other Aspergillus species, including closely related ones, such as A. parasiticus, A. nomius, and A. arachidicola. A. flavus is known to grow at the temperature of the human body (37°C), to produce bioactive secondary metabolites known as mycotoxins, and to tolerate high salinity levels, all of which are thought to be relevant for infection and growth in the human eye. However, we do not understand what genetic determinants of virulence are unique to A. flavus or how variation in these determinants contributes to within- and between-species variation in the ability of A. flavus to cause FK. The goal of my project is to understand what makes A. flavus a successful pathogen when other closely related, widespread Aspergillus species are not pathogenic as well as gain insights into variation in pathogenicity within A. flavus. I hypothesize that the A. flavus genome includes unique genetic determinants of virulence absent from related species. These may be genes or variants that are uniquely present or absent in A. flavus versus closely related non-pathogens, such as genes involved in secondary metabolism (secondary metabolites often affect host biology). We also do not yet know the genetic diversity, antifungal drug tolerance levels, or phenotypic responses to heat or salinity of FK-causing A. flavus isolates. I hypothesize that genetic and phenotypic traits differentially present in A. flavus and nonpathogenic relatives will also impact virulence. To test these hypotheses, I propose to first examine genomic diversity among Aspergillus species and within A. flavus to identify putative genetic determinants of virulence, and to examine the impact of unique determinants on virulence in an invertebrate model of disease. Second, I will investigate the impact of salinity, heat, and antifungal drugs on growth phenotypes and chemical profiles of A. flavus and related species, and to study the impact of secondary metabolites that are uniquely present in A. flavus on its virulence in an invertebrate model of disease. The proposed experiments will enable me to identify key differences in genetic elements between A. flavus and related species and provide a snapshot of population structure of clinical and environmental isolates within A. flavus, as well as characterize the physiological responses of A. flavus and related non-pathogenic species to infection-relevant conditions.

项目摘要 曲霉物种是人类真菌感染的主要原因，作为两者的疾病药物 曲霉病呼吸道感染和真菌性角膜炎（FK）眼感染。 FK需要角膜 移植或具有失明的毁灭性后果。报告了超过一百万个新案例的FK 每年一次。 FK的主要危险因素是眼睛的使用和表面划痕， 允许感染角膜；随着真菌生长到角膜时，会造成损害。 丝状真菌曲霉曲霉是FK感染的主要原因，并从FK中分离出来 角膜溃疡比任何其他曲霉物种都要高，包括紧密相关的物种，例如A。 Parasiticus，A。Nomius和A. Arachidicola。 A. Flavus已知会在人体温度下生长 （37°C），产生生物活性次级代谢产物，称为霉菌毒素，并耐受高盐度水平 其中被认为与人眼中的感染和生长有关。但是，我们不明白 哪种病毒的遗传决定因素是曲霉独有的，或这些决定因素的变异如何贡献 在曲霉引起fk的能力上的物种内和之间的差异。 我项目的目标是了解是什么使A. Flavus成为成功的病原体 相关的，宽度的曲霉物种不是致病性的，并且可以洞悉致病性的变化 在A. Flavus中。我假设A. flavus基因组包括缺乏病毒的独特遗传决定剂 来自相关物种。这些可能是在A. flavus中与众不同的基因或变体 密切相关的非毒素，例如涉及次级代谢的基因（次生代谢物通常 影响宿主生物学）。我们也不知道遗传多样性，抗真菌药物耐受水平或表型 对引起FK的热或盐度的反应。我假设遗传和表型性状 在黄曲曲霉和非人病亲戚中，存在不同的情况也会影响病毒。 为了检验这些假设，我建议在曲霉物种和 在黄曲霉内识别病毒的假定遗传决定剂，并检查独特的影响 无脊椎动物模型中病毒的决定因素。第二，我将调查盐度的影响， 热和抗真菌药物在生长表型和黄曲霉及相关物种的化学特征上，以及 研究a曲霉中唯一存在的二级代谢产物对无脊椎动物中病毒的影响 疾病模型。提出的实验将使我能够确定遗传元素的关键差异 在黄曲曲霉和相关物种之间，提供了临床人口结构的快照和 阿曲霉内的环境隔离株，并表征了阿曲霉的物理反应 相关的非致病物种与感染相关的条件。