PDF(Pubmed)
Abstract：
Previous studies from our laboratory and others have established the dendritic cell (DC) as a key target of RSV that drives infection-induced pathology. Analysis of RSV-induced transcriptomic changes in RSV-infected DC revealed metabolic gene signatures suggestive of altered cellular metabolism. Reverse phase protein array (RPPA) data showed significantly increased PARP1 phosphorylation in RSV-infected DC. Real-time cell metabolic analysis demonstrated increased glycolysis in PARP1-/- DC after RSV infection, confirming a role for PARP1 in regulating DC metabolism. Our data show that enzymatic inhibition or genomic ablation of PARP1 resulted in increased ifnb1, il12, and il27 in RSV-infected DC which, together, promote a more appropriate anti-viral environment. PARP1-/- mice and PARP1-inhibitor-treated mice were protected against RSV-induced immunopathology including airway inflammation, Th2 cytokine production, and mucus hypersecretion. However, delayed treatment with PARP1 inhibitor in RSV-infected mice provided only partial protection, suggesting that PARP1 is most important during the earlier innate immune stage of RSV infection.
摘要：
我们实验室和其他实验室的先前研究已将树突状细胞（DC）确立为RSV的关键靶标，可驱动感染诱导的病理学。RSV感染的DC中RSV诱导的转录组变化的分析揭示了代谢基因特征提示改变的细胞代谢。反相蛋白阵列(RPPA)数据显示RSV感染的DC中PARP1磷酸化显著增加。实时细胞代谢分析显示RSV感染后PARP1-/-DC糖酵解增加，确认PARP1在调节DC代谢中的作用。我们的数据显示，PARP1的酶抑制或基因组消融导致RSV感染的DC中ifnb1，il12和il27增加，一起,促进更合适的抗病毒环境。保护PARP1-/-小鼠和PARP1抑制剂治疗的小鼠免受RSV诱导的免疫病理学，包括气道炎症，Th2细胞因子产生，粘液分泌过多.然而,在RSV感染的小鼠中，PARP1抑制剂的延迟治疗仅提供部分保护，提示PARP1在RSV感染的早期先天性免疫阶段最为重要。
