School of Basic Medicine; Gannan Medical University, Ganzhou, Jiangxi.
School of Graduate, China Medical University, Shenyang, Liaoning.
J Immunol. 2024 Jun 15;212(12):1932-1944. doi: 10.4049/jimmunol.2300826.
IFN regulatory factor 7 (IRF7) exerts anti-infective effects by promoting the production of IFNs in various bacterial and viral infections, but its role in highly morbid and fatal Candida albicans infections is unknown. We unexpectedly found that Irf7 gene expression levels were significantly upregulated in tissues or cells after C. albicans infection in humans and mice and that IRF7 actually exacerbates C. albicans infection in mice independent of its classical function in inducing IFNs production. Compared to controls, Irf7-/- mice showed stronger phagocytosis of fungus, upregulation of C-type lectin receptor CD209 expression, and enhanced P53-AMPK-mTOR-mediated autophagic signaling in macrophages after C. albicans infection. The administration of the CD209-neutralizing Ab significantly hindered the phagocytosis of Irf7-/- mouse macrophages, whereas the inhibition of p53 or autophagy impaired the killing function of these macrophages. Thus, IRF7 exacerbates C. albicans infection by compromising the phagocytosis and killing capacity of macrophages via regulating CD209 expression and p53-AMPK-mTOR-mediated autophagy, respectively. This finding reveals a novel function of IRF7 independent of its canonical IFNs production and its unexpected role in enhancing fungal infections, thus providing more specific and effective targets for antifungal therapy.
干扰素调节因子 7 (IRF7) 通过促进各种细菌和病毒感染中 IFN 的产生发挥抗感染作用，但它在高致病性和致命性白色念珠菌感染中的作用尚不清楚。我们出人意料地发现，在人类和小鼠的白色念珠菌感染后，Irf7 基因表达水平在组织或细胞中显著上调，并且 IRF7 实际上独立于其诱导 IFN 产生的经典功能加剧了小鼠的白色念珠菌感染。与对照组相比，在白色念珠菌感染后，Irf7-/- 小鼠的吞噬作用更强，C 型凝集素受体 CD209 的表达上调，并且 P53-AMPK-mTOR 介导的自噬信号增强。用 CD209 中和 Ab 处理可显著抑制 Irf7-/- 小鼠巨噬细胞的吞噬作用，而抑制 p53 或自噬则损害这些巨噬细胞的杀伤功能。因此，IRF7 通过分别调节 CD209 表达和 P53-AMPK-mTOR 介导的自噬来损害巨噬细胞的吞噬和杀伤能力，从而加剧白色念珠菌感染。这一发现揭示了 IRF7 的一种新功能，独立于其经典的 IFN 产生，以及它在增强真菌感染中的意外作用，从而为抗真菌治疗提供了更特异和有效的靶点。
