School of Graduate, China Medical University, Shenyang, Liaoning, China.
School of Nursing, Gannan Medical University, Ganzhou, Jiangxi, China.
Cell Mol Life Sci. 2024 Jun 25;81(1):280. doi: 10.1007/s00018-024-05326-9.
Candida albicans is among the most prevalent invasive fungal pathogens for immunocompromised individuals and novel therapeutic approaches that involve immune response modulation are imperative. Absent in melanoma 2 (AIM2), a pattern recognition receptor for DNA sensing, is well recognized for its involvement in inflammasome formation and its crucial role in safeguarding the host against various pathogenic infections. However, the role of AIM2 in host defense against C. albicans infection remains uncertain. This study reveals that the gene expression of AIM2 is induced in human and mouse innate immune cells or tissues after C. albicans infection. Furthermore, compared to their wild-type (WT) counterparts, Aim2 mice surprisingly exhibit resistance to C. albicans infection, along with reduced inflammation in the kidneys post-infection. The resistance of Aim2 mice to C. albicans infection is not reliant on inflammasome or type I interferon production. Instead, Aim2 mice display lower levels of apoptosis in kidney tissues following infection than WT mice. The deficiency of AIM2 in macrophages, but not in dendritic cells, results in a phenocopy of the resistance observed in Aim2 mice against C. albican infection. The treatment of Clodronate Liposome, a reagent that depletes macrophages, also shows the critical role of macrophages in host defense against C. albican infection in Aim2 mice. Furthermore, the reduction in apoptosis is observed in Aim2 mouse macrophages following infection or treatment of DNA from C. albicans in comparison with controls. Additionally, higher levels of AKT activation are observed in Aim2 mice, and treatment with an AKT inhibitor reverses the host resistance to C. albicans infection. The findings collectively demonstrate that AIM2 exerts a negative regulatory effect on AKT activation and enhances macrophage apoptosis, ultimately compromising host defense against C. albicans infection. This suggests that AIM2 and AKT may represent promising therapeutic targets for the management of fungal infections.
白色念珠菌是免疫功能低下个体中最常见的侵袭性真菌病原体之一，因此需要寻找新的治疗方法，包括调节免疫反应。缺失在黑色素瘤 2（AIM2）中，一种用于 DNA 感应的模式识别受体，因其参与炎症小体的形成及其在保护宿主免受各种致病性感染方面的关键作用而得到广泛认可。然而，AIM2 在宿主防御白色念珠菌感染中的作用尚不确定。本研究表明，白色念珠菌感染后，人源和鼠源固有免疫细胞或组织中 AIM2 的基因表达被诱导。此外，与野生型（WT）相比，Aim2 小鼠对白色念珠菌感染表现出抗性，感染后肾脏的炎症反应减轻。Aim2 小鼠对白色念珠菌感染的抗性不依赖于炎症小体或 I 型干扰素的产生。相反，感染后 Aim2 小鼠肾脏组织中的细胞凋亡水平低于 WT 小鼠。巨噬细胞而非树突状细胞中 AIM2 的缺失导致了 Aim2 小鼠对白色念珠菌感染抗性的表型复制。用 Clodronate Liposome（一种消耗巨噬细胞的试剂）处理后，也显示了巨噬细胞在 Aim2 小鼠宿主防御白色念珠菌感染中的关键作用。此外，与对照组相比，感染或用白色念珠菌 DNA 处理后，Aim2 小鼠巨噬细胞中的细胞凋亡减少。此外，在 Aim2 小鼠中观察到 AKT 激活水平升高，并且 AKT 抑制剂的治疗逆转了宿主对白色念珠菌感染的抗性。这些发现表明，AIM2 对 AKT 激活具有负调节作用，并增强巨噬细胞凋亡，最终损害宿主防御白色念珠菌感染的能力。这表明 AIM2 和 AKT 可能成为管理真菌感染的有前途的治疗靶点。
