Abstract
Aspergillus fumigatus is a major fungal pathogen that is responsible for approximately 90% of human aspergillosis. Cofilin is an actin depolymerizing factor that plays crucial roles in multiple cellular functions in many organisms. However, the functions of cofilin in A. fumigatus are still unknown. In this study, we constructed an A. fumigatus strain overexpressing cofilin (cofilin OE). The cofilin OE strain displayed a slightly different growth phenotype, significantly increased resistance against H2O2 and diamide, and increased activation of the high osmolarity glycerol pathway compared to the wild-type strain (WT). The cofilin OE strain internalized more efficiently into lung epithelial A549 cells, and induced increased transcription of inflammatory factors (MCP-1, TNF-α and IL-8) compared to WT. Cofilin overexpression also resulted in increased polysaccharides including β-1, 3-glucan and chitin, and increased transcription of genes related to oxidative stress responses and polysaccharide synthesis in A. fumigatus. However, the cofilin OE strain exhibited similar virulence to the wild-type strain in murine and Galleria mellonella infection models. These results demonstrated for the first time that cofilin, a regulator of actin cytoskeleton dynamics, might play a critical role in the regulation of oxidative stress responses and cell wall polysaccharide synthesis in A. fumigatus.
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Acknowledgements
The authors thank Shuo Wang for technical assistance, Yong Chen for help with statistical analysis, and Xiaohong Wang for photography and illustrations. We are also grateful to Dr. Jean Paul Latge′ (Aspergillus Unit, Institut Pasteur, Paris, France) for providing the CEA17Δku80 strain and Dr. Johannes Wagener (Max von Pettenkofer-Institut für Hygiene und Medizinische Mikrobiologie, Ludwig-Maximilians-Universität München, 80336 Munich, Germany) for providing various plasmids. This work was supported by a Grants from the National Natural Science Foundation of China (No. 31400134), the 973 Program (No. 2013CB531606), and the National Natural Science Foundation of China (No. 81273230).
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All animal studies were approved by the Laboratory Animal Welfare and Ethics Committee of Academy of Military Medical Sciences (License Number IACUC-13-2016-002). According to the recommendations in the Guide for the Care and Use of Laboratory Animals of the Ministry of Science and Technology of the People’s Republic of China, infections were performed under isoflurane anesthesia, and all efforts were made to minimize suffering. Male BALB/c mice were obtained from the Fengtai Animal Center of Academy of Military Medical Sciences.
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Jia, X., Zhang, X., Hu, Y. et al. Role of actin depolymerizing factor cofilin in Aspergillus fumigatus oxidative stress response and pathogenesis. Curr Genet 64, 619–634 (2018). https://doi.org/10.1007/s00294-017-0777-5
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DOI: https://doi.org/10.1007/s00294-017-0777-5