Table_2_Xuebijing Injection Maintains GRP78 Expression to Prevent Candida albicans–Induced Epithelial Death in the Kidney.pdf

Sepsis and septic shock threaten the survival of millions of patients in the intensive care unit. Secondary fungal infections significantly increased the risk of mortality in sepsis patients. Chinese medicine Xuebijing injection (XBJ) has been routinely used as an add-on treatment to sepsis and septic shock in China. Our network pharmacology analysis predicted that XBJ also influences fungal infection, consisting with results of pioneer clinical studies. We conducted in vivo and in vitro experiments to verify this prediction. To our surprise, XBJ rescued mice from lethal Candida sepsis in a disseminated Candida albicans infection model and abolished the colonization of C. albicans in kidneys. Although XBJ did not inhibit the growth and the virulence of C. albicans in vitro, it enhanced the viability of 293T cells upon C. albicans insults. Further RNA-seq analysis revealed that XBJ activated the endoplasmic reticulum (ER) stress pathway upon C. albicans infection. Western blot confirmed that XBJ maintained the expression of GRP78 in the presence of C. albicans. Interestingly, key active ingredients in XBJ (C0127) mirrored the effects of XBJ. C0127 not only rescued mice from lethal Candida sepsis and prevented the colonization of C. albicans in kidneys, but also sustained the survival of kidney epithelial cells partially by maintaining the expression of GRP78. These results suggested that XBJ may prevent fungal infection in sepsis patients. Pre-activation of ER stress pathway is a novel strategy to control C. albicans infection. Network pharmacology may accelerate drug development in the field of infectious diseases.脓毒症与感染性休克严重威胁重症监护病房（Intensive Care Unit, ICU）中数百万患者的生存。继发性真菌感染会显著升高脓毒症患者的死亡风险。中药血必净注射液（Xuebijing Injection, XBJ）在中国被常规用作脓毒症与感染性休克的辅助治疗手段。我们通过网络药理学分析预测，血必净注射液同样可影响真菌感染进程，这与前期开创性临床研究的结果相符。我们开展了体内（in vivo）与体外（in vitro）实验以验证这一预测结果。令我们意外的是，在播散性白色念珠菌（Candida albicans）感染模型中，血必净注射液可使小鼠免于致死性念珠菌脓毒症，并消除白色念珠菌在小鼠肾脏中的定植。尽管血必净注射液在体外无法抑制白色念珠菌的生长与毒力，但可提升293T细胞在白色念珠菌侵袭后的存活率。进一步的RNA测序（RNA-seq）分析显示，在白色念珠菌感染后，血必净注射液可激活内质网（endoplasmic reticulum, ER）应激通路。蛋白质印迹（Western Blot）实验证实，在白色念珠菌存在的情况下，血必净注射液可维持葡萄糖调节蛋白78（Glucose-Regulated Protein 78, GRP78）的表达水平。有趣的是，血必净注射液中的关键活性成分C0127可复刻血必净注射液的作用效果。C0127不仅可使小鼠免于致死性念珠菌脓毒症、阻止白色念珠菌在肾脏中的定植，还可通过维持葡萄糖调节蛋白78的表达，部分提升肾上皮细胞的存活率。上述结果表明，血必净注射液或可预防脓毒症患者的真菌感染。预激活内质网应激通路是一种控制白色念珠菌感染的全新策略。网络药理学或可加速传染病领域的药物研发进程。