Gao Ru, Wang Heping, Cui Zhihui, Du Yanyun, He Ruirui, Feng Lingyun, Zeng Bo, Li Yangyang, Huang Guoling, Pan Ting, Wang Yuan, Yi Ming, Wang Chenhui
Key Laboratory of Molecular Biophysics of the Ministry of Education, National Engineering Research Center for Nanomedicine, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, China.
The Key Laboratory for Human Disease Gene Study of Sichuan Province and the Department of Laboratory Medicine, Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China.
PLoS Pathog. 2025 Jun 9;21(6):e1013179. doi: 10.1371/journal.ppat.1013179. eCollection 2025 Jun.
Invasive fungal infections (IFIs) have emerged as a significant health threat and cause approximately 3.75 million deaths per year globally. Understanding the detailed mechanism of the immune response to eliminate invasive fungal pathogens may help to provide new insights for the development of antifungal methods and drugs. Previously, we reported that the tyrosine kinase receptor EPH receptor B2 (EPHB2) is a coreceptor of β-glucan and phosphorylates Syk to activate the antifungal downstream signaling pathway. However, how EPHB2 is activated after fungal infection is still unknown. In this study, we show that EPHA5 plays a critical role in antifungal immunity by phosphorylating EPHB2 and Dectin-1 after fungal infection, which facilitates the recruitment and activation of Syk and subsequent activation of downstream antifungal signaling pathways. Additionally, we showed that EphA5-deficient mice exhibited increased susceptibility to Candida albicans infection, with increased fungal burdens and impaired immune cell recruitment. This study provides not only a mechanistic explanation for EPHB2 and Dectin-1 activation after fungal infection but also new insights into potential therapeutic strategies for treating IFIs.
侵袭性真菌感染（IFI）已成为对健康的重大威胁，全球每年约有375万人死于该疾病。了解消除侵袭性真菌病原体的免疫反应详细机制，可能有助于为抗真菌方法和药物的开发提供新见解。此前，我们报道酪氨酸激酶受体EPH受体B2（EPHB2）是β-葡聚糖的共受体，可磷酸化脾酪氨酸激酶（Syk）以激活抗真菌下游信号通路。然而，真菌感染后EPHB2如何被激活仍不清楚。在本研究中，我们发现EPH A5在真菌感染后通过磷酸化EPHB2和C型凝集素受体1（Dectin-1）在抗真菌免疫中起关键作用，这促进了Syk的募集和激活以及随后下游抗真菌信号通路的激活。此外，我们发现EphA5基因敲除小鼠对白色念珠菌感染的易感性增加，真菌负荷增加且免疫细胞募集受损。本研究不仅为真菌感染后EPHB2和Dectin-1的激活提供了机制解释，也为治疗IFI的潜在治疗策略提供了新见解。
