Analysis of pathways elicited by empty SV40 capsids (VLPs) in septic rats 24 hours post 2CLP operation

During the first hours after infection, before SV40 DNA enters the nucleus, empty capsids (VLPs) and the wild-type virus have the same effect on cellular signaling. VLPs were previously found to ameliorate toxic acute kidney injury (AKI) in a mouse model, counteracting apoptosis by inducing the Akt-1 survival pathway. Here we tested their effect on severe sepsis in rats. VLP pre-treatment increased survival and recovery from zero to 75%. RNAseq studies demonstrated that unlike AKI, here the VLPs did not induce survival pathways. Instead they affected thousands of genes and many cellular functions, eliminating deleterious pathways and inducing beneficial ones: immune response, resolution of inflammation, regeneration and cell and system homeostasis. In contrast, only four genes were affected following VLP administration to healthy rats. We propose that SV40 VLPs respond specifically to perturbation in cellular activities. The study suggests that diseases with complex pathophysiology may require treatments affecting wide-spectrum functions.在感染后的最初数小时内，于猿猴病毒40（SV40）DNA进入细胞核之前，空衣壳病毒样颗粒（VLPs）与野生型病毒对细胞信号通路的影响完全一致。既往研究证实，病毒样颗粒可在小鼠模型中缓解毒性急性肾损伤（AKI），通过激活Akt-1生存通路拮抗细胞凋亡。本研究就此探究了病毒样颗粒对大鼠重症脓毒症的作用效果。结果显示，病毒样颗粒预处理可将大鼠存活率从0提升至75%，并促进其恢复。RNA测序（RNAseq）研究表明，与急性肾损伤模型不同，本研究中的病毒样颗粒并未激活生存通路。相反，其可调控数千个基因及诸多细胞功能，清除有害信号通路并激活有益通路，涵盖免疫应答、炎症消退、组织再生以及细胞与系统稳态维持。与之形成对比的是，向健康大鼠给予病毒样颗粒后，仅4个基因的表达受到影响。本研究据此提出，猿猴病毒40病毒样颗粒可特异性响应细胞活动的紊乱。本研究提示，病理生理学机制复杂的疾病，或许需要影响广谱功能的治疗方案。