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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DOI：
10.1128/iai.00333-22
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发表时间：
2023-02-16
影响因子：
3.1
通讯作者：
Bignell E
中科院分区：
文献类型：
--
作者：
Okaa UJ;Bertuzzi M;Fortune-Grant R;Thomson DD;Moyes DL;Naglik JR;Bignell E
人的肺经常暴露于烟曲霉孢子，这是真菌性呼吸道疾病的最普遍的全球原因。肺组织损伤是肺吸虫相关疾病的一个统一特征;然而，损伤的机制基础尚不清楚。在易感宿主的肺中，A.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。我们模拟了A.在培养的A549人肺细胞中的烟曲霉感染，捕获五种宿主信号传导途径的磷酸活化状态，八种宿主转录因子的核转位和DNA结合，以及在包括暴露于活真菌及其分泌组的六个时间点内九种宿主应答蛋白的表达。由此产生的数据集，包括1,000多个数据点，揭示了肺细胞对A。烟曲霉孢子、菌丝和可溶性分泌产物分别通过NF-κB、JNK和JNK + p38途径。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），真菌分泌产物重新编排宿主对真菌挑战的反应，并驱动多参数上皮损伤，最终导致细胞溶解。NF-κB信号的失调，包括经典和非经典信号的顺序刺激，被确定为体外和侵袭性曲霉病小鼠模型中宿主损伤的重要特征。我们的数据表明，复合组织损伤的结果，从迭代（重复）暴露于不同的真菌形态和分泌的产品，并建议调制主机响应真菌的挑战可能代表一个统一的策略，用于治疗控制不同类型的真菌相关疾病。
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.
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影响因子：
2.9
作者：
Bertuzzi M;van Rhijn N;Krappmann S;Bowyer P;Bromley MJ;Bignell EM
通讯作者：
Bignell EM
口腔上皮细胞中MAPK/c-FOS诱导反应的激活特异于白色念珠菌和都柏林菌丝菌丝。
影响因子：
5.4
作者：
Moyes DL;Murciano C;Runglall M;Kohli A;Islam A;Naglik JR
通讯作者：
Naglik JR
影响因子：
3.6
作者：
Kupfahl, Claudio;Heinekamp, Thorsten;Brakhage, Axel A.
通讯作者：
Brakhage, Axel A.
影响因子：
3
作者：
Bellanger, Anne-Pauline;Millon, Laurence;Bretagne, Stephane
通讯作者：
Bretagne, Stephane
影响因子：
4.8
作者：
Fusco, Amanda J.;Savinova, Olga V.;Ghosh, Gourisankar
通讯作者：
Ghosh, Gourisankar