Gliotoxin promotes Aspergillus fumigatus internalization into type II human pneumocyte A549 cells by inducing host phospholipase D activation

Jia, Xiaodong; Chen, Fangyan; Pan, Weihua; Yu, Rentao; Tian, Shen; Han, Gaige; Fang, Haiqin; Wang, Shuo; Zhao, Jingya; Li, Xianping; Zheng, Dongyu; Tao, Shiquan; Liao, Wanqing; Han, Xiaonan; Han, Li

doi:10.1016/j.micinf.2014.03.001

Cited by 29 publications

(33 citation statements)

References 41 publications

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“…In previous studies we found that A . fumigatus conidia could induce obvious actin cytoskeleton rearrangement of A549 cells [ 11 – 12 ]. Interestingly, some up-regulated genes in this RNA-Seq analysis play important role in cytoskeleton remodeling, regulation of actin polymerization and morphological changes.…”

Section: Resultsmentioning

confidence: 99%

“…The nystatin protection assay to determine the A . fumigatus internalization into A549 cells were performed as previously described [ 11 – 12 ]. For the nystatin protection assay, A549 cells were seeded at 1 × 10 4 cells/well in 96-well plates (Corning) and grown for 16 h. The cells were incubated with A .…”

Section: Methodsmentioning

confidence: 99%

“…We have also demonstrated that A . fumigatus conidia can internalize into A549 cells and human bronchial epithelial cell line 16HBE14o, which is closely related to phospholipase D activation and actin cytoskeleton rearrangement in host cells [ 11 – 12 ]. The internalization of A .…”

Section: Introductionmentioning

confidence: 99%

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Transcriptome Profiles of Human Lung Epithelial Cells A549 Interacting with Aspergillus fumigatus by RNA-Seq

et al. 2015

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Lung epithelial cells constitute the first defense line of host against the inhaled Aspergillus fumigatus; however, the transcriptional response of human alveolar type II epithelial cells was still unclear. Here we used RNA-Seq technology to assess the transcriptome profiles of A549 cells following direct interaction with conidia of A. fumigatus. The total number of identified genes was 19118. Compared with uninfected A549 cells, 459 genes were differentially expressed in cells co-incubated with conidia for 8 h, including 302 up-regulated genes and 157 down-regulated genes. GO and KEGG pathway enrichment analysis showed that most of the up-regulated genes were related to immune response, chemotaxis and inflammatory response and enriched in cytokine-cytokine receptor interaction, JAK-STAT and MAPK signaling pathways. The down-regulated genes were mainly enriched for terms associated with development, hemopoiesis and ion transport. Among them, EGR4 and HIST1H4J gene had the maximum of fold change in up-regulated and down-regulated genes, respectively. Fourteen up-regulated genes and three down-regulated genes were further validated and significant increase on expression of IL-6, IL-8 and TNF-α in A549 cells were confirmed by qRT-PCR during the interaction of A549 cells with A. fumigatus. Besides, western blot showed that expression of two proteins (ARC, EGR1) significantly increased in A549 cells during interaction with A. fumigatus conidia for 8h. Interference of endogenous expression of ARC or EGR1 protein in A549 cells reduced the internalization of A. fumigatus. These results provided important insights into dynamic changes of gene expression in lung epithelial cells, especially its strong immunological response against A. fumigatus infection.

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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Transcriptome Profiles of Human Lung Epithelial Cells A549 Interacting with Aspergillus fumigatus by RNA-Seq

et al. 2015

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“…In the presence of GT a pronounced change in the neutrophil morphology (cell shrinkage) was observed with collapsed F‐actin around the nucleus indicated by large patches (Comera et al ., ). Internalization of A. fumigatus into epithelial cells through phospholipase D1 activation and actin cytoskeleton rearrangement was modulated by GT (Jia et al ., ). In contrast, endothelial cell stimulation by infection of A. fumigatus hyphae in vitro was not influenced by GT (Kamai et al ., ).…”

Section: Effects Of Gt On Cells and Potential Therapeutic Applicationsmentioning

confidence: 97%

Gliotoxin – bane or boon?

Scharf

Brakhage

Mukherjee

2015

Environmental Microbiology

102

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Summary Gliotoxin(GT) is the most important epidithiodioxopiperazine (ETP)-type fungal toxin. GT was originally isolated from Trichoderma species as an antibiotic substance involved in biological control of plant pathogenic fungi. A few isolates of GT-producing Trichoderma virens are commercially marketed for biological control and widely used in agriculture. Furthermore, GT is long known as an immunosuppressive agent and also reported to have anti-tumour properties. However, recent publications suggest that GT is a virulence determinant of the human pathogen Aspergillus fumigatus. This compound is thus important on several counts -it has medicinal properties, is a pathogenicity determinant, is a potential diagnostic marker and is important in biological crop protection. The present article addresses this paradox and the ecological role of GT. We discuss the function of GT as defence molecule, the role in aspergillosis and suggest solutions for safe application of Trichoderma-based biofungicides.

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“…Mycoviruses selectively infect fungi, are widely distributed in fungal groups, and typically possess RNA genomes. Some dsRNA mycoviruses of phytopathogenic fungi significantly decrease pathogenicity of their fungal hosts, suggesting great potential for control of the corresponding fungal diseases (Osaki et al, 2002;Hillman et al, 2004;Nuss, 2005;Chiba et al, 2009;Urayama et al, 2010;Wu et al, 2012;Jia et al, 2014). However, mycoviruses that reduce the virulence of fungal pathogens of animals and humans are not well-characterized, prohibiting the application of mycoviruses as therapeutic modalities for human fungal disease.…”

Section: Introductionmentioning

confidence: 99%

Analysis of an Intrinsic Mycovirus Associated With Reduced Virulence of the Human Pathogenic Fungus Aspergillus fumigatus

et al. 2020

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Aspergillus fumigatus is an airborne fungal pathogen that causes severe infections with invasive growth in immunocompromised patients. Several mycoviruses have recently been isolated from A. fumigatus strains, but there are presently no reports of mycoviralmediated reduction or elimination of fungal pathogenicity in vertebrate models. Here, we report the biological features of a novel mycovirus, A. fumigatus chrysovirus 41362 (AfuCV41362), isolated from the hypovirulent A. fumigatus strain IFM 41362. The AfuCV41362 genome is comprised of four dsRNAs, each of which contains a single ORF (ORF1-4). ORF1 encodes a protein with sequence similarity to RNA-dependent RNA polymerases of viruses in the family Chrysoviridae, while ORF3 encodes a putative capsid protein. Viral RNAs are expressed primarily during the germination stage, and RNA-seq analysis of virus-infected A. fumigatus at the germination stage suggested that the virus suppressed expression of several pathogenicity-associated host genes, including hypoxia adaptation and nitric oxide detoxification genes. In vitro functional analysis revealed that the virus-infected strain had reduced tolerance to environmental stressors. Virus-infected A. fumigatus strain IFM 41362 had reduced virulence in vivo compared to the virus-free strain in a mouse infection model. Furthermore, introduction of the mycovirus to a natively virus-free KU A. fumigatus strain induced virus-infected phenotypes. To identify mycovirus genes responsible for the reduced virulence of A. fumigatus, each viral ORF was ectopically expressed in the virus-free KU strain. Ectopic expression of the individual ORFs only nominally reduced virulence of the host fungus in a mouse infection model. However, we found that ORF3 and ORF4 reduced tolerance to environmental stresses in in vitro analysis. Based on these results, we suggest that the AfuCV41362 mycovirus ORF3 and ORF4 reduce fungal virulence by suppressing stress tolerance together with other viral genes, rather than alone.

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Gliotoxin promotes Aspergillus fumigatus internalization into type II human pneumocyte A549 cells by inducing host phospholipase D activation

Cited by 29 publications

References 41 publications

Transcriptome Profiles of Human Lung Epithelial Cells A549 Interacting with Aspergillus fumigatus by RNA-Seq

Transcriptome Profiles of Human Lung Epithelial Cells A549 Interacting with Aspergillus fumigatus by RNA-Seq

Gliotoxin – bane or boon?

Analysis of an Intrinsic Mycovirus Associated With Reduced Virulence of the Human Pathogenic Fungus Aspergillus fumigatus

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