Aspergillus fumigatus drives tissue damage via iterative assaults upon mucosal integrity and immune homeostasis
Aspergillus fumigatus drives tissue damage via iterative assaults upon mucosal integrity and immune homeostasis
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烟曲霉通过对粘膜完整性和免疫稳态的反复攻击来驱动组织损伤
DOI：
10.1101/2021.11.09.468003
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发表时间：
2021
期刊：
影响因子：
--
通讯作者：
Okaa U
中科院分区：
文献类型：
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作者：
Okaa U
人类肺部经常暴露于烟曲霉孢子，这是世界上最普遍的真菌呼吸系统疾病的原因。肺组织损伤是曲霉相关疾病的一个统一特征；然而，损伤的机制基础尚不清楚。在易感寄主的肺部，烟曲霉经历了一个强制性的形态转换，包括孢子萌发和菌丝生长。我们在培养的A549人肺细胞中模拟烟曲霉感染，捕捉5个宿主信号通路的磷酸化激活状态，8个宿主转录因子的核易位和DNA结合，以及9个宿主反应蛋白在6个时间点（包括暴露于活真菌及其分泌组）的表达。结果数据集由超过1000个数据点组成，揭示了肺细胞分别通过NF-κB、JNK和JNK + p38途径对烟曲霉孢子、菌丝和可溶性分泌产物产生不同的反应。重要的是，通过选择性降解宿主促炎（IL-6和IL-8）细胞因子和生长因子（FGF-2），真菌分泌产物重新协调宿主对真菌攻击的反应，并驱动多参数上皮损伤，最终导致细胞溶解。在体外和侵袭性曲霉病小鼠模型中，NF-κB信号的失调，包括典型和非典型信号的顺序刺激，被确定为宿主损伤的一个重要特征。我们的数据表明，复合组织损伤是由反复（重复）暴露于不同真菌形态和分泌产物造成的，并表明宿主对真菌攻击的反应调节可能代表了一种统一的策略，用于治疗控制病理上不同类型的曲霉相关疾病。
The human lung is constantly exposed to Aspergillus fumigatus spores, the most prevalent worldwide cause of fungal respiratory disease. Pulmonary tissue damage is a unifying feature of Aspergillus-related diseases; however, the mechanistic basis of damage is not understood. In the lungs of susceptible hosts, A. fumigatus undergoes an obligatory morphological switch involving spore germination and hyphal growth. We modeled A. fumigatus infection in cultured A549 human pneumocytes, capturing the phosphoactivation status of five host signaling pathways, nuclear translocation and DNA binding of eight host transcription factors, and expression of nine host response proteins over six time points encompassing exposures to live fungus and the secretome thereof. The resulting data set, comprised of more than 1,000 data points, reveals that pneumocytes mount differential responses to A. fumigatus spores, hyphae, and soluble secreted products via the NF-κB, JNK, and JNK + p38 pathways, respectively. Importantly, via selective degradation of host proinflammatory (IL-6 and IL-8) cytokines and growth factors (FGF-2), fungal secreted products reorchestrate the host response to fungal challenge as well as driving multiparameter epithelial damage, culminating in cytolysis. Dysregulation of NF-κB signaling, involving sequential stimulation of canonical and noncanonical signaling, was identified as a significant feature of host damage both in vitro and in a mouse model of invasive aspergillosis. Our data demonstrate that composite tissue damage results from iterative (repeated) exposures to different fungal morphotypes and secreted products and suggest that modulation of host responses to fungal challenge might represent a unified strategy for therapeutic control of pathologically distinct types of Aspergillus-related disease.