PDF(Pubmed)
Abstract：
During pulmonary mucormycosis, inhaled sporangiospores adhere to, germinate, and invade airway epithelial cells to establish infection. We provide evidence that HIF1α plays dual roles in airway epithelial cells during Mucorales infection. We observed an increase in HIF1α protein accumulation and increased expression of many known HIF1α-responsive genes during in vitro infection, indicating that HIF1α signaling is activated by Mucorales infection. Inhibition of HIF1α signaling led to a substantial decrease in the ability of R. delemar to invade cultured airway epithelial cells. Transcriptome analysis revealed that R. delemar infection induces the expression of many pro-inflammatory genes whose expression was significantly reduced by HIF1α inhibition. Importantly, pharmacological inhibition of HIF1α increased survival in a mouse model of pulmonary mucormycosis without reducing fungal burden. These results suggest that HIF1α plays two opposing roles during mucormycosis: one that facilitates the ability of Mucorales to invade the host cells and one that facilitates the ability of the host to mount an innate immune response.
摘要：
在肺毛霉菌病期间，吸入的孢子孢子粘附，发芽,并侵入气道上皮细胞建立感染。我们提供的证据表明，HIF1α在Mucorales感染期间在气道上皮细胞中起双重作用。我们观察到在体外感染期间HIF1α蛋白积累的增加和许多已知的HIF1α反应基因的表达增加。表明HIF1α信号传导被毛霉菌感染激活。HIF1α信号传导的抑制导致R.delemar侵入培养的气道上皮细胞的能力大大降低。转录组分析显示R.delemar感染诱导许多促炎基因的表达，这些基因的表达被HIF1α抑制显着降低。重要的是,药物抑制HIF1α可增加肺毛霉菌病小鼠模型的存活率，而不减少真菌负担。这些结果表明，HIF1α在毛霉菌病中起着两种相反的作用：一种促进毛霉菌侵入宿主细胞的能力，另一种促进宿主建立先天免疫反应的能力。
