Prusty Bhupesh Kumar, Hollmann Claudia, Park Eun Chan, Liu Zheng, Nourollahi Faye, Nikolayshvili Georgy, Dietz Jonathan, Bašēns Emils, Vora Mehul, Waghmare Trushnal, Li Tongbin, Imdahl Fabian, Rongo Christopher
Riga Stradins University.
Julius-Maximilians University of Würzburg.
Res Sq. 2025 Jul 29:rs.3.rs-7077811. doi: 10.21203/rs.3.rs-7077811/v1.
Multiple mechanisms of immunity must be coordinated to defend against a comprehensive range of pathogens; however, the mechanisms by which broad-spectrum antipathogens act remain largely elusive. Here, we employed systems biology approaches to understand the organization of human immune cells at the single-cell level, as well as their reorganization in response to K21, a silane derivative effective against viral, bacterial, and fungal infections. K21 induced pro-inflammatory pathways in M1 and M2c macrophages without altering cytokine secretion, decreased a specific subtype of M1 macrophages and CXCL4-induced M2-like macrophages, and improved mitochondrial health by enhancing mitochondrial recycling via mitophagy. Similar treatment of the model organism induced mitophagy and extended lifespan, suggesting evolutionary conservation of mechanism. Our work demonstrates that a drug that remodels mitochondria and metabolism can shape the immune cell repertoire, which could aid the development of more effective antimicrobials and prevent the emergence of drug-resistant pathogens.
必须协调多种免疫机制以抵御各种各样的病原体；然而，广谱抗病原体发挥作用的机制在很大程度上仍然难以捉摸。在这里，我们采用系统生物学方法来了解人类免疫细胞在单细胞水平上的组织情况，以及它们在应对K21（一种对病毒、细菌和真菌感染有效的硅烷衍生物）时的重组情况。K21在M1和M2c巨噬细胞中诱导促炎途径，但不改变细胞因子分泌，减少M1巨噬细胞的特定亚型和CXCL4诱导的M2样巨噬细胞，并通过增强线粒体自噬来改善线粒体健康。对模式生物进行类似处理可诱导线粒体自噬并延长寿命，这表明该机制具有进化保守性。我们的工作表明，一种重塑线粒体和代谢的药物可以塑造免疫细胞库，这有助于开发更有效的抗菌药物，并防止耐药病原体的出现。
