Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, MD, 21201, USA.
Division of Infectious Diseases, The Lundquist Institute for Biomedical Innovation, Harbor-UCLA Medical Center, Torrance, CA, 90502, USA.
Nat Commun. 2024 Jun 20;15(1):5282. doi: 10.1038/s41467-024-49637-8.
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.
在肺部毛霉病中，吸入的孢子附着、发芽并侵入气道上皮细胞，从而引发感染。我们提供的证据表明，HIF1α 在毛霉目感染的气道上皮细胞中发挥双重作用。我们观察到，在体外感染过程中，HIF1α 蛋白积累增加，许多已知的 HIF1α 反应基因的表达增加，表明 HIF1α 信号通路被毛霉目感染激活。抑制 HIF1α 信号通路导致 R. delemar 侵入培养的气道上皮细胞的能力显著下降。转录组分析显示，R. delemar 感染诱导许多促炎基因的表达，而这些基因的表达被 HIF1α 抑制显著降低。重要的是，HIF1α 的药理学抑制作用增加了肺部毛霉病小鼠模型的存活率，而不会降低真菌负担。这些结果表明，HIF1α 在毛霉病中发挥两种相反的作用：一种作用是促进毛霉目侵入宿主细胞的能力，另一种作用是促进宿主产生先天免疫反应的能力。
