Aspergillus fumigatus calcium-responsive transcription factors regulate cell wall architecture promoting stress tolerance, virulence and caspofungin resistance.,PLOS Genetics

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Aspergillus fumigatus calcium-responsive transcription factors regulate cell wall architecture promoting stress tolerance, virulence and caspofungin resistance.
PLOS Genetics ( IF 4.0 ) Pub Date : 2019-12-30 , DOI: 10.1371/journal.pgen.1008551
Patrícia Alves de Castro ₁ , Ana Cristina Colabardini ₁ , Adriana Oliveira Manfiolli ₁ , Jéssica Chiaratto ₁ , Lilian Pereira Silva ₁ , Eliciane Cevolani Mattos ₁ , Giuseppe Palmisano ₂ , Fausto Almeida ₃ , Gabriela Felix Persinoti ₄ , Laure Nicolas Annick Ries ₃ , Laura Mellado ₁ , Marina Campos Rocha ₅ , Michael Bromley ₆ , Roberto Nascimento Silva ₃ , Gabriel Scalini de Souza ₇ , Flávio Vieira Loures ₇ , Iran Malavazi ₅ , Neil Andrew Brown ₈ , Gustavo H Goldman ₁

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Aspergillus fumigatus causes invasive aspergillosis, the most common life-threatening fungal disease of immuno-compromised humans. The treatment of disseminated infections with antifungal drugs, including echinocandin cell wall biosynthesis inhibitors, is increasingly challenging due to the rise of drug-resistant pathogens. The fungal calcium responsive calcineurin-CrzA pathway influences cell morphology, cell wall composition, virulence, and echinocandin resistance. A screen of 395 A. fumigatus transcription factor mutants identified nine transcription factors important to calcium stress tolerance, including CrzA and ZipD. Here, comparative transcriptomics revealed CrzA and ZipD regulated the expression of shared and unique gene networks, suggesting they participate in both converged and distinct stress response mechanisms. CrzA and ZipD additively promoted calcium stress tolerance. However, ZipD also regulated cell wall organization, osmotic stress tolerance and echinocandin resistance. The absence of ZipD in A. fumigatus caused a significant virulence reduction in immunodeficient and immunocompetent mice. The ΔzipD mutant displayed altered cell wall organization and composition, while being more susceptible to macrophage killing and eliciting an increased pro-inflammatory cytokine response. A higher number of neutrophils, macrophages and activated macrophages were found in ΔzipD infected mice lungs. Collectively, this shows that ZipD-mediated regulation of the fungal cell wall contributes to the evasion of pro-inflammatory responses and tolerance of echinocandin antifungals, and in turn promoting virulence and complicating treatment options.

中文翻译：

烟曲霉钙反应转录因子调节细胞壁结构，促进应激耐受性、毒力和卡泊芬净抗性。

烟曲霉引起侵袭性曲霉病，这是免疫功能低下的人类最常见的危及生命的真菌病。由于耐药病原体的增加，使用抗真菌药物（包括棘白菌素细胞壁生物合成抑制剂）治疗播散性感染变得越来越具有挑战性。真菌钙反应性钙调神经磷酸酶-CrzA 途径影响细胞形态、细胞壁组成、毒力和棘白菌素耐药性。对 395 个烟曲霉转录因子突变体的筛选鉴定出 9 个对钙胁迫耐受性重要的转录因子，包括 CrzA 和 ZipD。在这里，比较转录组学揭示了 CrzA 和 ZipD 调节共享和独特基因网络的表达，表明它们参与聚合和不同的应激反应机制。 CrzA 和 ZipD 进一步促进钙胁迫耐受性。然而，ZipD 还调节细胞壁组织、渗透应激耐受性和棘白菌素抗性。烟曲霉中 ZipD 的缺失导致免疫缺陷和免疫功能正常小鼠的毒力显着降低。 ΔzipD突变体表现出改变的细胞壁组织和组成，同时更容易受到巨噬细胞杀伤并引发促炎细胞因子反应增强。在 ΔzipD 感染的小鼠肺部发现了更多数量的中性粒细胞、巨噬细胞和活化的巨噬细胞。总的来说，这表明 ZipD 介导的真菌细胞壁调节有助于逃避促炎反应和棘白菌素抗真菌药物的耐受性，进而促进毒力并使治疗方案复杂化。

更新日期：2019-12-31

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