Wang Guizhen, Liu Yan, Li Qianyu, Wang Changhui, Fang Wei
Department of Emergency, Shanghai, Tenth People's Hospital, School of Medicine Tongji University, Shanghai, China.
Department of Clinical Laboratory, Shanghai Tenth People's Hospital, School of Medicine Tongji University, Shanghai, China.
Mycology. 2025 Feb 3;16(3):1373-1385. doi: 10.1080/21501203.2025.2453739. eCollection 2025.
The dynamic interplay between pathogens and host immune system determines the outcome of fungal infections. This study investigates the role of Ubp5 in modulating host defenses during H99 infections. Ubp5 deletion significantly reduces both pulmonary invasion and extrapulmonary dissemination, resulting in prolonged survival and decreased fungal burdens in mice. Attenuated virulence is closely associated with enhanced host immune responses, rather than diminished pathogen fitness alone. Histopathological and leukocyte analyses revealed a shift towards protective adaptive immune responses in Δ-infected lungs, characterized by lymphocyte-dominated inflammatory infiltration and an increased Th1/Th17 cytokine response. Under host-associated conditions, Δ mutants exhibited morphological changes, including distorted shapes and cell wall heterogeneity, alongside defects in key virulence factors such as the polysaccharide capsule and melanin. These changes likely promote exposure of immunostimulatory cell wall components, enhancing host immunity. Additionally, Ubp5 deletion resulted in a significant reduction in intracellular ribosomal particles in , which likely impairs protein synthesis, contributing to reduced growth and pathogenic fitness . These findings underscore the pivotal role of Ubp5 in maintaining cryptococcal virulence and suggest that targeting Ubp5 could enhance host immunity against cryptococcosis by promoting protective immune responses and limiting fungal dissemination.
病原体与宿主免疫系统之间的动态相互作用决定了真菌感染的结果。本研究调查了Ubp5在H99感染期间调节宿主防御中的作用。Ubp5缺失显著减少了肺部侵袭和肺外播散，导致小鼠存活时间延长和真菌负荷降低。毒力减弱与宿主免疫反应增强密切相关，而不仅仅是病原体适应性降低。组织病理学和白细胞分析显示，感染Δ的肺部向保护性适应性免疫反应转变，其特征是以淋巴细胞为主的炎症浸润和Th1/Th17细胞因子反应增加。在与宿主相关的条件下，Δ突变体表现出形态变化，包括形状扭曲和细胞壁异质性，以及多糖荚膜和黑色素等关键毒力因子的缺陷。这些变化可能促进免疫刺激细胞壁成分的暴露，增强宿主免疫力。此外，Ubp5缺失导致细胞内核糖体颗粒显著减少，这可能损害蛋白质合成，导致生长和致病适应性降低。这些发现强调了Ubp5在维持新型隐球菌毒力中的关键作用，并表明靶向Ubp5可通过促进保护性免疫反应和限制真菌播散来增强宿主对隐球菌病的免疫力。
