A possible role for fumagillin in cellular damage during host infection by Aspergillus fumigatus
Virulence mechanisms of the pathogenic fungus Aspergillus fumigatus are multifactorial and depend on the immune state of the host, but little is known about the fungal mechanism that develops during the process of lung invasion. In this study, microarray technology was combined with a histopathology...
| Main Authors: | , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Taylor & Francis Group
2018-12-01
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| Series: | Virulence |
| Subjects: | |
| Online Access: | http://dx.doi.org/10.1080/21505594.2018.1526528 |
| _version_ | 1811201051544518656 |
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| author | Xabier Guruceaga Guillermo Ezpeleta Emilio Mayayo Monica Sueiro-Olivares Ana Abad-Diaz-De-Cerio José Manuel Aguirre Urízar Hong G. Liu Philipp Wiemann Jin Woo Bok Scott G. Filler Nancy P. Keller Fernando L. Hernando Andoni Ramirez-Garcia Aitor Rementeria |
| author_facet | Xabier Guruceaga Guillermo Ezpeleta Emilio Mayayo Monica Sueiro-Olivares Ana Abad-Diaz-De-Cerio José Manuel Aguirre Urízar Hong G. Liu Philipp Wiemann Jin Woo Bok Scott G. Filler Nancy P. Keller Fernando L. Hernando Andoni Ramirez-Garcia Aitor Rementeria |
| author_sort | Xabier Guruceaga |
| collection | DOAJ |
| description | Virulence mechanisms of the pathogenic fungus Aspergillus fumigatus are multifactorial and depend on the immune state of the host, but little is known about the fungal mechanism that develops during the process of lung invasion. In this study, microarray technology was combined with a histopathology evaluation of infected lungs so that the invasion strategy followed by the fungus could be described. To achieve this, an intranasal mice infection was performed to extract daily fungal samples from the infected lungs over four days post-infection. The pathological study revealed a heavy fungal progression throughout the lung, reaching the blood vessels on the third day after exposure and causing tissue necrosis. One percent of the fungal genome followed a differential expression pattern during this process. Strikingly, most of the genes of the intertwined fumagillin/pseurotin biosynthetic gene cluster were upregulated as were genes encoding lytic enzymes such as lipases, proteases (DppIV, DppV, Asp f 1 or Asp f 5) and chitinase (chiB1) as well as three genes related with pyomelanin biosynthesis process. Furthermore, we demonstrate that fumagillin is produced in an in vitro pneumocyte cell line infection model and that loss of fumagillin synthesis reduces epithelial cell damage. These results suggest that fumagillin contributes to tissue damage during invasive aspergillosis. Therefore, it is probable that A. fumigatus progresses through the lungs via the production of the mycotoxin fumagillin combined with the secretion of lytic enzymes that allow fungal growth, angioinvasion and the disruption of the lung parenchymal structure. |
| first_indexed | 2024-04-12T02:15:28Z |
| format | Article |
| id | doaj.art-2f401884faf044bb8f5ce754b968ea69 |
| institution | Directory Open Access Journal |
| issn | 2150-5594 2150-5608 |
| language | English |
| last_indexed | 2024-04-12T02:15:28Z |
| publishDate | 2018-12-01 |
| publisher | Taylor & Francis Group |
| record_format | Article |
| series | Virulence |
| spelling | doaj.art-2f401884faf044bb8f5ce754b968ea692022-12-22T03:52:17ZengTaylor & Francis GroupVirulence2150-55942150-56082018-12-01911548156110.1080/21505594.2018.15265281526528A possible role for fumagillin in cellular damage during host infection by Aspergillus fumigatusXabier Guruceaga0Guillermo Ezpeleta1Emilio Mayayo2Monica Sueiro-Olivares3Ana Abad-Diaz-De-Cerio4José Manuel Aguirre Urízar5Hong G. Liu6Philipp Wiemann7Jin Woo Bok8Scott G. Filler9Nancy P. Keller10Fernando L. Hernando11Andoni Ramirez-Garcia12Aitor Rementeria13University of the Basque Country (UPV/EHU)Complejo Hospitalario de NavarraUniversity of Rovira i Virgili, ReusUniversity of the Basque Country (UPV/EHU)University of the Basque Country (UPV/EHU)University of the Basque Country (UPV/EHU)Los Angeles Biomedical Research Institute at Harbor-UCLA Medical CenterUniversity of WisconsinUniversity of WisconsinLos Angeles Biomedical Research Institute at Harbor-UCLA Medical CenterUniversity of WisconsinUniversity of the Basque Country (UPV/EHU)University of the Basque Country (UPV/EHU)University of the Basque Country (UPV/EHU)Virulence mechanisms of the pathogenic fungus Aspergillus fumigatus are multifactorial and depend on the immune state of the host, but little is known about the fungal mechanism that develops during the process of lung invasion. In this study, microarray technology was combined with a histopathology evaluation of infected lungs so that the invasion strategy followed by the fungus could be described. To achieve this, an intranasal mice infection was performed to extract daily fungal samples from the infected lungs over four days post-infection. The pathological study revealed a heavy fungal progression throughout the lung, reaching the blood vessels on the third day after exposure and causing tissue necrosis. One percent of the fungal genome followed a differential expression pattern during this process. Strikingly, most of the genes of the intertwined fumagillin/pseurotin biosynthetic gene cluster were upregulated as were genes encoding lytic enzymes such as lipases, proteases (DppIV, DppV, Asp f 1 or Asp f 5) and chitinase (chiB1) as well as three genes related with pyomelanin biosynthesis process. Furthermore, we demonstrate that fumagillin is produced in an in vitro pneumocyte cell line infection model and that loss of fumagillin synthesis reduces epithelial cell damage. These results suggest that fumagillin contributes to tissue damage during invasive aspergillosis. Therefore, it is probable that A. fumigatus progresses through the lungs via the production of the mycotoxin fumagillin combined with the secretion of lytic enzymes that allow fungal growth, angioinvasion and the disruption of the lung parenchymal structure.http://dx.doi.org/10.1080/21505594.2018.1526528Aspergillusfumagillinintranasal infectionAWAFUGEepithelial cellsfumagillincytotoxicityvirulence |
| spellingShingle | Xabier Guruceaga Guillermo Ezpeleta Emilio Mayayo Monica Sueiro-Olivares Ana Abad-Diaz-De-Cerio José Manuel Aguirre Urízar Hong G. Liu Philipp Wiemann Jin Woo Bok Scott G. Filler Nancy P. Keller Fernando L. Hernando Andoni Ramirez-Garcia Aitor Rementeria A possible role for fumagillin in cellular damage during host infection by Aspergillus fumigatus Virulence Aspergillus fumagillin intranasal infection AWAFUGE epithelial cells fumagillin cytotoxicity virulence |
| title | A possible role for fumagillin in cellular damage during host infection by Aspergillus fumigatus |
| title_full | A possible role for fumagillin in cellular damage during host infection by Aspergillus fumigatus |
| title_fullStr | A possible role for fumagillin in cellular damage during host infection by Aspergillus fumigatus |
| title_full_unstemmed | A possible role for fumagillin in cellular damage during host infection by Aspergillus fumigatus |
| title_short | A possible role for fumagillin in cellular damage during host infection by Aspergillus fumigatus |
| title_sort | possible role for fumagillin in cellular damage during host infection by aspergillus fumigatus |
| topic | Aspergillus fumagillin intranasal infection AWAFUGE epithelial cells fumagillin cytotoxicity virulence |
| url | http://dx.doi.org/10.1080/21505594.2018.1526528 |
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