S. aureus drives itch and scratch-induced skin damage through a V8 protease-PAR1 axis

IF 45.5 1区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Cell Pub Date : 2023-11-22 DOI:10.1016/j.cell.2023.10.019

Liwen Deng, Flavia Costa, Kimbria J. Blake, Samantha Choi, Arundhasa Chandrabalan, Muhammad Saad Yousuf, Stephanie Shiers, Daniel Dubreuil, Daniela Vega-Mendoza, Corinne Rolland, Celine Deraison, Tiphaine Voisin, Michelle D. Bagood, Lucia Wesemann, Abigail M Frey, Joseph S. Palumbo, Brian J. Wainger, Richard L. Gallo, Juan-Manuel Leyva-Castillo, Nathalie Vergnolle, Isaac M. Chiu

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引用次数: 2

Abstract

Itch is an unpleasant sensation that evokes a desire to scratch. The skin barrier is constantly exposed to microbes and their products. However, the role of microbes in itch generation is unknown. Here, we show that Staphylococcus aureus, a bacterial pathogen associated with itchy skin diseases, directly activates pruriceptor sensory neurons to drive itch. Epicutaneous S. aureus exposure causes robust itch and scratch-induced damage. By testing multiple isogenic bacterial mutants for virulence factors, we identify the S. aureus serine protease V8 as a critical mediator in evoking spontaneous itch and alloknesis. V8 cleaves proteinase-activated receptor 1 (PAR1) on mouse and human sensory neurons. Targeting PAR1 through genetic deficiency, small interfering RNA (siRNA) knockdown, or pharmacological blockade decreases itch and skin damage caused by V8 and S. aureus exposure. Thus, we identify a mechanism of action for a pruritogenic bacterial factor and demonstrate the potential of inhibiting V8-PAR1 signaling to treat itch.

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金黄色葡萄球菌通过V8蛋白酶- par1轴驱动瘙痒和划伤引起的皮肤损伤

痒是一种令人不愉快的感觉，它唤起了挠痒的欲望。皮肤屏障经常暴露在微生物及其产物中。然而，微生物在瘙痒产生中的作用尚不清楚。在这里，我们发现金黄色葡萄球菌，一种与瘙痒性皮肤病相关的细菌病原体，直接激活瘙痒感受器感觉神经元来驱动瘙痒。表皮金黄色葡萄球菌暴露引起强烈的瘙痒和划伤引起的损害。通过检测多个等基因细菌突变体的毒力因子，我们发现金黄色葡萄球菌丝氨酸蛋白酶V8是引发自发性瘙痒和异位反应的关键介质。V8在小鼠和人的感觉神经元上切割蛋白酶激活受体1 (PAR1)。通过基因缺陷、小干扰RNA (siRNA)敲低或药物阻断靶向PAR1可减少V8和金黄色葡萄球菌暴露引起的瘙痒和皮肤损伤。因此，我们确定了致痒细菌因子的作用机制，并证明了抑制V8-PAR1信号通路治疗瘙痒的潜力。

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来源期刊

Cell 生物-生化与分子生物学

CiteScore

110.00

自引率

0.80%

发文量

396

审稿时长

2 months

期刊介绍： Cells is an international, peer-reviewed, open access journal that focuses on cell biology, molecular biology, and biophysics. It is affiliated with several societies, including the Spanish Society for Biochemistry and Molecular Biology (SEBBM), Nordic Autophagy Society (NAS), Spanish Society of Hematology and Hemotherapy (SEHH), and Society for Regenerative Medicine (Russian Federation) (RPO). The journal publishes research findings of significant importance in various areas of experimental biology, such as cell biology, molecular biology, neuroscience, immunology, virology, microbiology, cancer, human genetics, systems biology, signaling, and disease mechanisms and therapeutics. The primary criterion for considering papers is whether the results contribute to significant conceptual advances or raise thought-provoking questions and hypotheses related to interesting and important biological inquiries. In addition to primary research articles presented in four formats, Cells also features review and opinion articles in its "leading edge" section, discussing recent research advancements and topics of interest to its wide readership.