Mechanism(s) of pathogenicity for Candida auris

耳念珠菌的致病机制

• 批准号: 10328232
• 负责人: Jeniel E Nett
• 金额: $ 53.4万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-02-01 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10328232
• 关键词: Antifungal Agents; Candida; Candida auris; Candidiasis; Carbohydrates; Cell Surface Receptors; Cell Wall; Cell surface; Collection; Data; Development; Disease; Disease Outbreaks; Drug resistance; Exhibits; Fungal Components; Future; Genetic; Goals; Hospitals; Human; Hybrids; Hydrolysis; Immune; Immune Evasion; Immune System Diseases; Immune response; Immunotherapy; Impairment; Individual; Label; Laboratories; Light; Mannans; Membrane Glycoproteins; Modeling; Modification; Molecular; Mycoses; Natural Immunity; Neutropenia; Pathogenesis; Pathogenicity; Pattern; Pattern recognition receptor; Phagocytosis; Pharmacology; Public Health; Rattus; Refractory; Reporting; Risk; Role; Testing; Therapeutic; Virulence; Virulent; Yeasts; Zebrafish; base; design; drug resistant pathogen; emerging pathogen; extracellular; fungus; global health; imaging study; in vivo; innovation; mannoproteins; mortality; multi-drug resistant pathogen; mutant; neutrophil; new therapeutic target; novel strategies; novel therapeutic intervention; overexpression; pathogenic fungus; receptor; receptor expression; recruit; response; therapeutic development; therapeutic target; uptake

PROJECT SUMMARY The emerging fungal pathogen Candida auris has produced numerous outbreaks of invasive disease in hospitals worldwide. With mortality rates as high as 60%, the continued rise of this drug-resistant pathogen is alarming. Further understanding of the unexpected virulence of C. auris is desperately needed for the design of innovative therapeutic approaches. My laboratory’s long-term goal is to find new approaches to understand, detect, and treat invasive fungal infections. The objective of this application is to delineate how C. auris evades innate immunity and to develop a novel therapeutic strategy to circumvent this mechanism. We have found that neutrophils, leukocytes critical for control of many invasive fungal infections, fail to kill C. auris. We propose that uncovering the molecular mechanism of this immune evasion will identify new drug targets. Our preliminary data provide compelling evidence for the involvement of a C. auris cell wall component. Furthermore, we have identified a subset of neutrophils with enhanced antifungal activity. We plan to capitalize on this finding to delineate the molecular aspects of a successful neutrophil response against C. auris. This will not only shed light on the virulence of C. auris, but will also establish a platform for future neutrophil-based immunotherapies. We anticipate this approach will have broad implications for the treatment of a variety of drug-resistant or treatment-refractory invasive fungal infections.

项目总结 新出现的真菌病原体金黄色念珠菌在 世界各地的医院。随着死亡率高达60%，这种耐药病原体的持续上升 令人担忧。迫切需要进一步了解金黄色葡萄球菌出乎意料的毒力。 设计创新的治疗方法。我的实验室的长期目标是找到新的方法来 了解、检测和治疗侵袭性真菌感染。本应用程序的目标是描述如何 C.Auris逃避天然免疫，并开发一种新的治疗策略来规避这一机制。 我们已经发现，中性粒细胞，控制许多侵袭性真菌感染的关键白细胞，不能杀死 C.Auris。我们认为，揭示这种免疫逃避的分子机制将发现新的 毒品目标。我们的初步数据为金黄色葡萄球菌细胞壁的参与提供了令人信服的证据。 组件。此外，我们还鉴定了一组具有增强抗真菌活性的中性粒细胞。我们 计划利用这一发现来描绘成功的中性粒细胞反应的分子方面 对阵C.Auris。这不仅将揭示金黄色葡萄球菌的毒力，而且还将为 未来以中性粒细胞为基础的免疫疗法。我们预计这种方法将对 治疗各种耐药或难治性侵袭性真菌感染。