Mechanism(s) of pathogenicity for Candida auris

耳念珠菌的致病机制

• 批准号: 10092934
• 负责人: Jeniel E Nett
• 金额: $ 53.33万
• 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/10092934
• 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.

项目摘要 新出现的真菌病原体耳念珠菌已经在非洲引起了许多侵袭性疾病的爆发。 全球医院随着死亡率高达60%，这种抗药性病原体的持续上升， 令人担忧进一步了解C.奥里斯是迫切需要的， 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， 了解、检测和治疗侵袭性真菌感染。本申请的目的是描述如何 C.耳回避先天免疫，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，白细胞的关键控制许多侵袭性真菌感染，不能杀死 C.耳。我们认为，揭示这种免疫逃避的分子机制将发现新的 药物靶点我们的初步数据为C.耳细胞壁 成分此外，我们已经确定了一个子集的中性粒细胞增强抗真菌活性。我们 我计划利用这一发现来描述成功的中性粒细胞应答的分子方面 针对C.耳。这不仅有助于阐明C.但也将建立一个平台， 未来的免疫疗法。我们预计这种方法将对 治疗多种耐药性或难治性侵袭性真菌感染。