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 曲霉菌属是人类真菌感染的主要原因， 曲霉病呼吸道感染和真菌性角膜炎（FK）眼部感染。FK可能需要角膜 移植或失明的毁灭性后果。报告了超过100万的新病例 每年在世界各地。FK的主要风险因素是使用隐形透镜和眼睛表面划痕， 使角膜受到感染;当真菌长入角膜时发生损害。 丝状真菌黄曲霉是FK感染的主要原因，并从FK中分离 角膜溃疡的发生率高于其他曲霉属，包括密切相关的曲霉属，如A. parasiticus、A. nomius和A.花生。A.已知黄曲霉菌在人体温度下生长 (37°C），产生生物活性次级代谢产物，称为真菌毒素，并耐受高盐度水平，所有 其中的一种被认为与人眼中的感染和生长有关。但是，我们不明白 什么样的致病基因决定了A. flavus或这些决定因素的变化如何影响 种内和种间的差异，A. flavus引起FK。 我的项目的目标是了解是什么使A。当其他病原体与黄曲霉菌密切相关时， 相关的、广泛分布的曲霉属物种不是致病性的，并且获得对致病性变化的了解 在A.黄色的我假设A.黄病毒基因组包括独特的遗传决定因素的毒力缺失 相关物种。这些可以是在A中唯一存在或不存在的基因或变体。黄与 密切相关的非病原体，如参与次级代谢的基因（次级代谢物通常 影响宿主生物学）。我们也还不知道遗传多样性，抗真菌药物耐受水平，或表型 引起FK的A.黄曲霉分离物我假设遗传和表型特征 差异存在于A.黄病毒和非致病性亲缘病毒也会影响毒力。 为了验证这些假设，我建议首先检查曲霉属物种之间的基因组多样性， 在A.黄曲霉毒素，以确定推定的毒力遗传决定因素，并检查独特的影响， 在无脊椎动物疾病模型中的毒力决定因素。其次，我将研究盐度的影响， 加热和抗真菌药物对A. flavus和相关物种，以及 研究次级代谢产物的影响，这些次级代谢产物是唯一存在于A.黄曲霉对无脊椎动物的毒性 疾病的模型。拟议中的实验将使我能够确定遗传因素的关键差异 在A.和相关物种，并提供了临床和 环境分离物在A. flavus的生理反应，并对A.黄色和 将非致病性物种与感染相关病症相关联。