The Aspergillus fumigatus unfolded protein response (UPR) is a two-component relay consisting of the ER-bound IreA protein, which splices and activates the mRNA of the transcription factor HacA. Spliced hacA accumulates under conditions of acute ER stress in vitro, and UPR null mutants are hypovirulent in a murine model of invasive pulmonary infection. In this report, we demonstrate that a hacA deletion mutant (ΔhacA) is furthermore avirulent in a model of fungal keratitis, a corneal infection, and an important cause of ocular morbidity and unilateral blindness worldwide. Interestingly, we demonstrate that A. fumigatus hacA is spliced in infected lung samples, but not in the cornea, suggesting the amount of ER stress experienced by the fungus varies upon the host niche. To better understand how the UPR contributes to fungal cell biology across a spectrum of ER-stress levels, we employed transcriptomics on the wild-type and ΔhacA strains in glucose minimal media (low stress), glucose minimal media with dithiothreitol (high stress), and gelatin minimal media as a proxy for the nutrient stress encountered in the cornea (mid-level stress). These data altogether reveal a unique HacA-dependent transcriptome under each condition, suggesting that HacA activity is finely-tuned and required for proper fungal adaptation in each environment. Taken together, our results indicate that the fungal UPR could serve as an important antifungal target in the setting of both invasive pulmonary and corneal infections.

中文翻译：

---

烟曲霉 UPR 在营养和宿主环境中的激活程度不同，对于角膜感染的建立至关重要。

烟曲霉未折叠蛋白反应 (UPR) 是一个由 ER 结合的 IreA 蛋白组成的双组分中继，该蛋白可剪接并激活转录因子 HacA 的 mRNA。剪接的 hacA 在体外急性 ER 应激条件下积累，UPR 无效突变体在侵袭性肺部感染的小鼠模型中呈低毒力。在本报告中，我们证明 hacA 缺失突变体 (ΔhacA) 在真菌性角膜炎、角膜感染以及全球眼部发病和单侧失明的重要原因模型中无毒力。有趣的是，我们证明烟曲霉 hacA 在受感染的肺部样本中剪接，但不在角膜中剪接，这表明真菌经历的 ER 应激量因宿主生态位而异。为了更好地了解 UPR 如何在一系列 ER 应激水平下对真菌细胞生物学做出贡献，我们对葡萄糖基本培养基（低应激）、含有二硫苏糖醇的葡萄糖基本培养基（高应激）中的野生型和 ΔhacA 菌株进行了转录组学分析。和明胶基本培养基作为角膜中遇到的营养应激（中等应激）的代表。这些数据共同揭示了每种条件下独特的 HacA 依赖性转录组，表明 HacA 活性经过微调，并且是真菌在每种环境中适当适应所必需的。综上所述，我们的结果表明，真菌 UPR 可以作为侵袭性肺部和角膜感染的重要抗真菌靶点。