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，当猿猴空泡病毒40（Simian Virus 40, SV40）的DNA尚未进入细胞核时，空衣壳（病毒样颗粒，virus-like particles, VLPs）与野生型病毒对细胞信号通路的影响完全一致。此前已有研究证实，VLPs可在小鼠模型中缓解中毒性急性肾损伤（acute kidney injury, AKI），通过激活Akt-1生存通路抑制细胞凋亡。本研究在此基础上探究了VLPs对大鼠重症脓毒症的干预效果：VLPs预处理可使大鼠存活率与康复率从0提升至75%。RNA测序（RNA sequencing, RNA-seq）研究显示，与AKI的情况不同，VLPs在此并未激活生存通路。相反，它们可调控数千个基因与诸多细胞功能，清除有害通路并激活有益通路，包括免疫应答、炎症消退、组织再生以及细胞与系统稳态维持。与之形成鲜明对比的是，将VLPs给予健康大鼠后，仅4个基因的表达受到影响。我们据此提出，SV40来源的VLPs可特异性响应细胞活动的异常扰动。本研究提示，对于病理生理机制复杂的疾病，或许需要可调控广谱功能的治疗手段。