title: Gliotoxin promotes Aspergillus fumigatus internalization into type II human pneumocyte A549 cells by inducing host phospholipase D activation.
abstract: The internalization of Aspergillus fumigatus into lung epithelial cells is critical for the infection process in the host. Gliotoxin is the most potent toxin produced by A. fumigatus. However, its role in A. fumigatus internalization into the lung epithelial cells is still largely unknown. In the present study, the deletion of the gliP gene regulating the production of gliotoxin in A. fumigatus suppressed the internalization of conidia into the A549 lung epithelial cells, and this suppression could be rescued by the exogenous addition of gliotoxin. At lower concentrations, gliotoxin enhanced the internalization of the conidia of A. fumigatus into A549 cells; in contrast, it inhibited the phagocytosis of J774 macrophages in a dose-dependent manner. Under a concentration of 100 ng/ml, gliotoxin had no effect on A549 cell viability but attenuated ROS production in a dose-dependent manner. Gliotoxin significantly stimulated the phospholipase D activity in the A549 cells at a concentration of 50 ng/ml. This stimulation was blocked by the pretreatment of host cells with PLD1- but not PLD2-specific inhibitor. Morphological cell changes induced by gliotoxin were observed in the A549 cells accompanying with obvious actin cytoskeleton rearrangement and a moderate alteration of phospholipase D distribution. Our data indicated that gliotoxin might be responsible for modulating the A. fumigatus internalization into epithelial cells through phospholipase D1 activation and actin cytoskeleton rearrangement.
authors.affiliation: Department for Hospital Infection Control & Research, Institute of Disease Control & Prevention of PLA, Academy of Military Medical Sciences, Beijing, China.
authors.forename: Xiaodong
authors.initials: X
authors.lastname: Jia
authors.affiliation: Department for Hospital Infection Control & Research, Institute of Disease Control & Prevention of PLA, Academy of Military Medical Sciences, Beijing, China.
authors.forename: Fangyan
authors.initials: F
authors.lastname: Chen
authors.affiliation: Shanghai Key Laboratory of Molecular Mycology, Department of Dermatology, Shanghai Changzheng Hospital, Second Military Medical University, Shanghai, China.
authors.forename: Weihua
authors.initials: W
authors.lastname: Pan
authors.affiliation: Department for Hospital Infection Control & Research, Institute of Disease Control & Prevention of PLA, Academy of Military Medical Sciences, Beijing, China; Patent Examination Cooperation Center of the Patent Office, Beijing, China.
authors.forename: Rentao
authors.initials: R
authors.lastname: Yu
authors.affiliation: Department for Hospital Infection Control & Research, Institute of Disease Control & Prevention of PLA, Academy of Military Medical Sciences, Beijing, China.
authors.forename: Shuguang
authors.initials: S
authors.lastname: Tian
authors.affiliation: Department for Hospital Infection Control & Research, Institute of Disease Control & Prevention of PLA, Academy of Military Medical Sciences, Beijing, China.
authors.forename: Gaige
authors.initials: G
authors.lastname: Han
authors.affiliation: Department for Hospital Infection Control & Research, Institute of Disease Control & Prevention of PLA, Academy of Military Medical Sciences, Beijing, China.
authors.forename: Haiqin
authors.initials: H
authors.lastname: Fang
authors.affiliation: Department for Hospital Infection Control & Research, Institute of Disease Control & Prevention of PLA, Academy of Military Medical Sciences, Beijing, China.
authors.forename: Shuo
authors.initials: S
authors.lastname: Wang
authors.affiliation: Department for Hospital Infection Control & Research, Institute of Disease Control & Prevention of PLA, Academy of Military Medical Sciences, Beijing, China.
authors.forename: Jingya
authors.initials: J
authors.lastname: Zhao
authors.affiliation: Department for Hospital Infection Control & Research, Institute of Disease Control & Prevention of PLA, Academy of Military Medical Sciences, Beijing, China.
authors.forename: Xianping
authors.initials: X
authors.lastname: Li
authors.affiliation: Department for Hospital Infection Control & Research, Institute of Disease Control & Prevention of PLA, Academy of Military Medical Sciences, Beijing, China.
authors.forename: Dongyu
authors.initials: D
authors.lastname: Zheng
authors.affiliation: Department for Hospital Infection Control & Research, Institute of Disease Control & Prevention of PLA, Academy of Military Medical Sciences, Beijing, China.
authors.forename: Sha
authors.initials: S
authors.lastname: Tao
authors.affiliation: Shanghai Key Laboratory of Molecular Mycology, Department of Dermatology, Shanghai Changzheng Hospital, Second Military Medical University, Shanghai, China.
authors.forename: Wanqing
authors.initials: W
authors.lastname: Liao
authors.affiliation: Department for Hospital Infection Control & Research, Institute of Disease Control & Prevention of PLA, Academy of Military Medical Sciences, Beijing, China. Electronic address: yilin791228@126.com.
authors.forename: Xuelin
authors.initials: X
authors.lastname: Han
authors.affiliation: Department for Hospital Infection Control & Research, Institute of Disease Control & Prevention of PLA, Academy of Military Medical Sciences, Beijing, China. Electronic address: hanli@bmi.ac.cn.
authors.forename: Li
authors.initials: L
authors.lastname: Han
mesh_terms: D008841:Actin Cytoskeleton / Q000378:metabolism; D056809:Alveolar Epithelial Cells / Q000201:enzymology / Q000382:microbiology*; D001232:Aspergillus fumigatus / Q000235:genetics / Q000472:pathogenicity*; D045744:Cell Line, Tumor; D002470:Cell Survival; D017353:Gene Deletion; D005912:Gliotoxin / Q000737:chemistry*; D054884:Host-Pathogen Interactions; D006801:Humans; D008168:Lung / Q000166:cytology / Q000378:metabolism; D010587:Phagocytosis; D010739:Phospholipase D / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D017382:Reactive Oxygen Species; D005912:Gliotoxin; D010739:Phospholipase D; C106801:phospholipase D1
keywords: Aspergillus fumigatus; Gliotoxin; Internalization; Phospholipase D