Tetz Victor, Kardava Kristina, Vecherkovskaya Maria, Khodadadi-Jamayran Alireza, Tsirigos Aristotelis, Tetz George
bioRxiv. 2024 Dec 20:2024.12.17.628964. doi: 10.1101/2024.12.17.628964.
Despite recent advances, the regulation of anticancer and antimicrobial bioactive compound (AABC) production by leukocytes remains poorly understood. Here, we demonstrate that inactivation of the DNA- and RNA-based Teazeled receptors of the Universal Receptive System in human leukocytes generated so called "Leukocyte-Tells," which showed enhanced AABC production. Comprehensive analysis of the AABCs produced by Leukocyte-Tells based on LC/MS identified 707 unique or differentially produced peptide or non-peptide metabolites. Functional testing demonstrated that many of these metabolites exhibited increased antibacterial, antifungal, and anticancer activities. The AABCs produced by the Leukocyte-Tells were effective against different multidrug-resistant clinical isolates of fungi and gram-positive and gram-negative bacteria (including their biofilms), as well as various cancer cell lines, with >100,000-fold activity than AABCs derived from control leukocytes. Notably, the AABCs produced by the Leukocyte-Tells exhibited greater stability under adverse environmental conditions. Our findings highlight the important role of the Universal Receptive System in regulating AABC production through a process named here as cell genome memory management, offering new insights into immune functions and suggesting potential therapeutic applications.
The Universal Receptive System acts as a novel regulator of biosynthetic activity in leukocytes. Modulating the leukocyte Universal Receptive System by inactivating Teazeled receptors triggers the production of new compounds not observed in naïve cells. We refer to these TezR-modified cells as "Leukocyte-Tells." Leukocytes produce unique metabolites with strong anticancer and antimicrobial activities. Reproducibility in generating leukocytes from the blood of different donors suggests that the observed alterations in cell activity were preprogrammed.
尽管最近取得了进展，但白细胞对抗癌和抗菌生物活性化合物（AABC）产生的调控仍知之甚少。在这里，我们证明，人类白细胞中通用受体系统基于DNA和RNA的起绒草受体失活会产生所谓的“白细胞信号”，其显示出增强的AABC产生。基于液相色谱/质谱对白细胞信号产生的AABC进行的综合分析鉴定出707种独特的或差异产生的肽或非肽代谢物。功能测试表明，这些代谢物中的许多都表现出增强的抗菌、抗真菌和抗癌活性。白细胞信号产生的AABC对不同的耐多药临床分离真菌、革兰氏阳性和革兰氏阴性细菌（包括它们的生物膜）以及各种癌细胞系有效，其活性比对照白细胞来源的AABC高100,000倍以上。值得注意的是，白细胞信号产生的AABC在不利环境条件下表现出更高的稳定性。我们的研究结果突出了通用受体系统在通过此处称为细胞基因组记忆管理的过程调节AABC产生中的重要作用，为免疫功能提供了新见解，并暗示了潜在的治疗应用。
通用受体系统作为白细胞生物合成活性的新型调节剂。通过使起绒草受体失活来调节白细胞通用受体系统会触发幼稚细胞中未观察到的新化合物的产生。我们将这些经TezR修饰的细胞称为“白细胞信号”。白细胞产生具有强大抗癌和抗菌活性的独特代谢物。从不同供体的血液中生成白细胞的可重复性表明，观察到的细胞活性变化是预先编程的。
