Pathogen-induced inflammation is attenuated by the iminosugar MON-DNJ via modulation of the unfolded protein response

Sepsis is a life-threatening condition involving a dysregulated immune response to infectious agents that causes injury to host tissues and organs. Current treatments are limited to early administration of antibiotics and supportive care. While appealing, the strategy of targeted inhibition of individual molecules in the inflammatory cascade has not proved beneficial. Non-targeted, systemic immunosuppression with steroids has shown limited efficacy and raises concern for secondary infection. Iminosugars are a class of small molecule glycomimetics with distinct inhibition profiles for glycan processing enzymes based on stereochemistry. Inhibition of host endoplasmic reticulum resident glycoprotein processing enzymes has demonstrated efficacy as a broad spectrum antiviral strategy, but limited consideration has been given to the effects on host glycoprotein production and consequent disruption of signaling cascades. This work demonstrates that iminosugars inhibit dengue virus, bacterial lipopolysaccharide, and fungal antigen stimulated cytokine responses in human macrophages. In spite of decreased inflammatory mediator production, viral replication is suppressed in the presence of iminosugar. Transcriptome analysis reveals the key interaction of pathogen-induced endoplasmic reticulum stress, the resulting unfolded protein response, and inflammation. Our work shows that iminosugars modulate these interactions. Based on these findings, we propose a new therapeutic role for iminosugars as treatment for sepsis related inflammatory disorders associated with excess cytokine secretion.

脓毒症（Sepsis）是一种危及生命的疾病，其本质是宿主对病原体产生失调的免疫应答，进而导致宿主组织与器官损伤。当前治疗手段仅局限于早期抗生素给药与支持治疗。尽管靶向抑制炎症级联反应中的单个分子颇具吸引力，但该策略尚未被证实有效；而使用糖皮质激素的非靶向全身免疫抑制疗法疗效有限，且存在继发感染风险。亚氨基糖（Iminosugars）是一类小分子糖模拟物，基于立体化学结构可对糖加工酶展现出独特的抑制谱。靶向抑制宿主内质网驻留糖蛋白加工酶的策略已被证实可作为广谱抗病毒手段，但此前针对其影响宿主糖蛋白生成及后续信号级联紊乱的研究尚显不足。本研究证实，亚氨基糖可在人巨噬细胞中抑制登革病毒、细菌脂多糖及真菌抗原刺激诱导的细胞因子应答。尽管炎症介质的生成有所减少，但亚氨基糖存在时病毒复制仍可被抑制。转录组分析揭示了病原体诱导的内质网应激、由此产生的未折叠蛋白反应与炎症反应之间的关键互作机制，本研究表明亚氨基糖可调控上述三者的相互作用。基于上述发现，我们提出亚氨基糖可作为治疗伴随细胞因子过度分泌的脓毒症相关炎症性疾病的新型治疗策略。