Department of Ophthalmology and Visual Sciences, Case Western Reserve University, Cleveland, OH 44106, USA.
J Clin Invest. 2012 Jul;122(7):2482-98. doi: 10.1172/JCI63239. Epub 2012 Jun 18.
Filamentous fungi are a common cause of blindness and visual impairment worldwide. Using both murine model systems and in vitro human neutrophils, we found that NADPH oxidase produced by neutrophils was essential to control the growth of Aspergillus and Fusarium fungi in the cornea. We demonstrated that neutrophil oxidant production and antifungal activity are dependent on CD18, but not on the β-glucan receptor dectin-1. We used mutant A. fumigatus strains to show that the reactive oxygen species-sensing transcription factor Yap1, superoxide dismutases, and the Yap1-regulated thioredoxin antioxidant pathway are each required for protection against neutrophil-mediated oxidation of hyphae as well as optimal survival of fungal hyphae in vivo. We also demonstrated that thioredoxin inhibition using the anticancer drug PX-12 increased the sensitivity of fungal hyphae to both H2O2- and neutrophil-mediated killing in vitro. Additionally, topical application of PX-12 significantly enhanced neutrophil-mediated fungal killing in infected mouse corneas. Cumulatively, our data reveal critical host oxidative and fungal anti-oxidative mediators that regulate hyphal survival during infection. Further, these findings also indicate that targeting fungal anti-oxidative defenses via PX-12 may represent an efficacious strategy for treating fungal infections.
丝状真菌是全球范围内导致失明和视力损害的常见原因。通过使用小鼠模型系统和体外人类中性粒细胞，我们发现中性粒细胞产生的 NADPH 氧化酶对于控制角膜中曲霉菌和镰刀菌真菌的生长至关重要。我们证明中性粒细胞氧化剂的产生和抗真菌活性依赖于 CD18，但不依赖于β-葡聚糖受体 dectin-1。我们使用突变的烟曲霉菌株表明，活性氧感应转录因子 Yap1、超氧化物歧化酶和 Yap1 调节的硫氧还蛋白抗氧化途径对于防止中性粒细胞介导的菌丝氧化以及真菌菌丝在体内的最佳存活都是必需的。我们还证明，使用抗癌药物 PX-12 抑制硫氧还蛋白可增加真菌菌丝对 H2O2 和中性粒细胞介导的杀伤的敏感性。此外，局部应用 PX-12 可显著增强感染小鼠角膜中中性粒细胞介导的真菌杀伤作用。总的来说，我们的数据揭示了调节感染过程中菌丝存活的关键宿主氧化和真菌抗氧化介质。此外，这些发现还表明，通过 PX-12 靶向真菌抗氧化防御可能是治疗真菌感染的有效策略。
