Shepardson Kelly M, Jhingran Anupam, Caffrey Alayna, Obar Joshua J, Suratt Benjamin T, Berwin Brent L, Hohl Tobias M, Cramer Robert A
Department of Microbiology and Immunology, Geisel School of Medicine at Dartmouth, Hanover, New Hampshire, United States of America.
Infectious Disease Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York, United States of America.
PLoS Pathog. 2014 Sep 25;10(9):e1004378. doi: 10.1371/journal.ppat.1004378. eCollection 2014 Sep.
Hypoxia inducible factor 1α (HIF1α) is the mammalian transcriptional factor that controls metabolism, survival, and innate immunity in response to inflammation and low oxygen. Previous work established that generation of hypoxic microenvironments occurs within the lung during infection with the human fungal pathogen Aspergillus fumigatus. Here we demonstrate that A. fumigatus stabilizes HIF1α protein early after pulmonary challenge that is inhibited by treatment of mice with the steroid triamcinolone. Utilizing myeloid deficient HIF1α mice, we observed that HIF1α is required for survival and fungal clearance early following pulmonary challenge with A. fumigatus. Unlike previously reported research with bacterial pathogens, HIF1α deficient neutrophils and macrophages were surprisingly not defective in fungal conidial killing. The increase in susceptibility of the myeloid deficient HIF1α mice to A. fumigatus was in part due to decreased early production of the chemokine CXCL1 (KC) and increased neutrophil apoptosis at the site of infection, resulting in decreased neutrophil numbers in the lung. Addition of recombinant CXCL1 restored neutrophil survival and numbers, murine survival, and fungal clearance. These results suggest that there are unique HIF1α mediated mechanisms employed by the host for protection and defense against fungal pathogen growth and invasion in the lung. Additionally, this work supports the strategy of exploring HIF1α as a therapeutic target in specific immunosuppressed populations with fungal infections.
缺氧诱导因子1α（HIF1α）是一种哺乳动物转录因子，可响应炎症和低氧来控制代谢、生存及固有免疫。先前的研究表明，在感染人类真菌病原体烟曲霉期间，肺内会形成缺氧微环境。在此，我们证明，烟曲霉在肺部攻击后早期可使HIF1α蛋白稳定，而用类固醇曲安西龙治疗小鼠可抑制这种稳定作用。利用髓系细胞缺乏HIF1α的小鼠，我们观察到，在用烟曲霉进行肺部攻击后早期，HIF1α对生存和真菌清除是必需的。与先前关于细菌病原体的研究不同，令人惊讶的是，HIF1α缺乏的中性粒细胞和巨噬细胞在杀死真菌分生孢子方面并无缺陷。髓系细胞缺乏HIF1α的小鼠对烟曲霉易感性增加，部分原因是趋化因子CXCL1（KC）的早期产生减少，以及感染部位中性粒细胞凋亡增加，导致肺内中性粒细胞数量减少。添加重组CXCL1可恢复中性粒细胞的生存和数量、小鼠的生存以及真菌清除。这些结果表明，宿主采用了独特的HIF1α介导机制来保护和抵御肺部真菌病原体的生长和侵袭。此外，这项工作支持了将HIF1α作为特定真菌感染免疫抑制人群治疗靶点的策略探索。
