髓细胞PTP1B缺乏通过调节抗真菌免疫增加对白色念珠菌全身感染的易感性。

IF 4.7 1区 生物学 Q1 MICROBIOLOGY
mBio Pub Date : 2025-10-08 Epub Date: 2025-08-29 DOI:10.1128/mbio.01516-25
Bethany Allen, Ivy M Dambuza, Susan H Berry, Delyth M Reid, Sam M McVey, Martina Mesiarikova, Larissa John, Moira Davie, Christa P Baker, J Simon C Arthur, Mirela Delibegovic, Gordon D Brown, Heather M Wilson
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引用次数: 0

摘要

侵袭性念珠菌病主要由白色念珠菌引起,对免疫功能低下的患者构成重大威胁,死亡率高。了解对白色念珠菌的免疫反应是如何建立和控制的是开发新的治疗策略的基础。蛋白酪氨酸磷酸酶1B (PTP1B)是免疫受体信号和下游炎症和代谢反应的调节因子,也是一个药物靶点。在这里,我们揭示了髓细胞内在PTP1B在抗真菌免疫中的关键作用。骨髓细胞中缺乏PTP1B (LysM PTP1B-/-)的小鼠明显更容易受到全身性白色念珠菌感染,表现出更低的存活率,更大的体重减轻,以及肾脏、肝脏和大脑中真菌负荷的增加。这些小鼠还显示器官中促炎mRNA表达升高,肾小管炎症增加,白细胞浸润和趋化因子产生增加,导致免疫病理。来自LysM PTP1B-/-小鼠的中性粒细胞在感染肾脏中表现出成熟受损和体外活性氧产生减少。受感染骨髓源性巨噬细胞(bmdm)的蛋白质组学分析显示,在缺乏PTP1B的情况下,I型干扰素调节蛋白显著富集。这些BMDMs在感染期间表现出吞噬功能受损、杀伤能力降低和生存能力降低,这些表型在PTP1B药理学抑制剂治疗的人巨噬细胞中重现。总的来说,我们的研究结果强调了PTP1B作为先天免疫应答白色念珠菌的关键调节剂,在抗真菌活性和全身毒性与炎症和代谢适应性之间取得平衡。增强特异性ptp1b依赖通路可能为增强宿主防御提供新的策略,同时最大限度地减少真菌诱导的免疫病理。全身性白色念珠菌感染是医院获得性发病率和死亡率的主要原因,特别是在免疫功能低下的个体和接受免疫抑制治疗的患者中。尽管抗真菌治疗,结果仍然很差,强调需要更好地了解控制真菌清除的宿主因素。蛋白酪氨酸磷酸酶1B (PTP1B)是细胞内免疫和代谢信号的关键调节因子。本研究确定髓系PTP1B在抗真菌防御和对全身白色念珠菌感染的易感性中起关键作用。PTP1B的缺失会损害中性粒细胞和巨噬细胞的功能,破坏炎症平衡,并损害病原体的清除。这些发现揭示了PTP1B作为对白色念珠菌免疫反应的中枢调节剂,并突出了其作为宿主定向治疗靶点的潜力,以改善全身性真菌感染的结果。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
PTP1B deficiency in myeloid cells increases susceptibility to Candida albicans systemic infection by modulating antifungal immunity.

Invasive candidiasis, primarily caused by Candida albicans, poses a significant threat to immunocompromised patients, with high mortality rates. Understanding how immune responses to Candida albicans are mounted and controlled is fundamental to developing new therapeutic strategies. Protein tyrosine phosphatase 1B (PTP1B) is a regulator of immunoreceptor signaling and downstream inflammatory and metabolic responses and a pharmaceutical target. Here, we reveal a critical role for myeloid cell-intrinsic PTP1B in antifungal immunity. Mice lacking PTP1B in myeloid cells (LysM PTP1B-/-) were significantly more susceptible to systemic C. albicans infection, exhibiting lower survival, greater weight loss, and elevated fungal burdens in the kidney, liver, and brain. These mice also showed heightened proinflammatory mRNA expression in organs and increased kidney tubular inflammation, with increased leukocyte infiltration and chemokine production, contributing to immunopathology. Neutrophils from LysM PTP1B-/- mice displayed impaired maturation in infected kidneys and reduced reactive oxygen species production in vitro. Proteomic profiling of infected bone marrow-derived macrophages (BMDMs) revealed significant enrichment of type I interferon-regulated proteins in the absence of PTP1B. These BMDMs showed impaired phagocytosis, reduced killing capacity, and lower viability during infection, phenotypes recapitulated in human macrophages treated with a pharmacological PTP1B inhibitor. Collectively, our findings highlight PTP1B as a key modulator of innate immune responses to C. albicans, balancing antifungal activity and systemic toxicity with inflammation and metabolic fitness. Boosting specific PTP1B-dependent pathways may offer new strategies for enhancing host defense while minimizing fungal-induced immunopathology.IMPORTANCESystemic Candida albicans infections are a leading cause of hospital-acquired morbidity and mortality, particularly in immunocompromised individuals and patients receiving immunosuppressive treatments. Despite antifungal therapies, outcomes remain poor, underscoring the need to better understand host factors that control fungal clearance. Protein tyrosine phosphatase 1B (PTP1B) is a key intracellular regulator of immune and metabolic signaling. This study identifies a critical role for myeloid PTP1B in antifungal defense and susceptibility to systemic C. albicans infection. Loss of PTP1B impairs neutrophil and macrophage function, disrupts inflammatory balance, and compromises pathogen clearance. These findings reveal PTP1B as a central modulator of immune responses to C. albicans and highlight its potential as a target for host-directed therapies to improve outcomes in systemic fungal infections.

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来源期刊
mBio
mBio MICROBIOLOGY-
CiteScore
10.50
自引率
3.10%
发文量
762
审稿时长
1 months
期刊介绍: mBio® is ASM''s first broad-scope, online-only, open access journal. mBio offers streamlined review and publication of the best research in microbiology and allied fields.
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