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Urease of Aspergillus fumigatus Is Required for Survival in Macrophages and Virulence

The number of patients suffering from fungal diseases has constantly increased during the last decade. Among the fungal pathogens, the airborne filamentous fungus Aspergillus fumigatus can cause chronic and fatal invasive mold infections. So far, only three major classes of drugs (polyenes, azoles,...

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Autores principales: Xiong, Zhenzhen, Zhang, Nan, Xu, Liru, Deng, Zhiduo, Limwachiranon, Jarukitt, Guo, Yaojie, Han, Yi, Yang, Wei, Scharf, Daniel H.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Society for Microbiology 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10100864/
https://www.ncbi.nlm.nih.gov/pubmed/36916906
http://dx.doi.org/10.1128/spectrum.03508-22
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author Xiong, Zhenzhen
Zhang, Nan
Xu, Liru
Deng, Zhiduo
Limwachiranon, Jarukitt
Guo, Yaojie
Han, Yi
Yang, Wei
Scharf, Daniel H.
author_facet Xiong, Zhenzhen
Zhang, Nan
Xu, Liru
Deng, Zhiduo
Limwachiranon, Jarukitt
Guo, Yaojie
Han, Yi
Yang, Wei
Scharf, Daniel H.
author_sort Xiong, Zhenzhen
collection PubMed
description The number of patients suffering from fungal diseases has constantly increased during the last decade. Among the fungal pathogens, the airborne filamentous fungus Aspergillus fumigatus can cause chronic and fatal invasive mold infections. So far, only three major classes of drugs (polyenes, azoles, and echinocandins) are available for the treatment of life-threatening fungal infections, and all present pharmacological drawbacks (e.g., low solubility or toxicity). Meanwhile, clinical antifungal-resistant isolates are continuously emerging. Therefore, there is a high demand for novel antifungal drugs, preferentially those that act on new targets. We studied urease and the accessory proteins in A. fumigatus to determine their biochemical roles and their influence on virulence. Urease is crucial for the growth on urea as the sole nitrogen source, and the transcript and protein levels are elevated on urea media. The urease deficient mutant displays attenuated virulence, and its spores are more susceptible to macrophage-mediated killing. We demonstrated that this observation is associated with an inability to prevent the acidification of the phagosome. Furthermore, we could show that a nickel-chelator inhibits growth on urea. The nickel chelator is also able to reverse the effects of urease on macrophage killing and phagosome acidification, thereby reducing virulence in systemic and trachea infection models. IMPORTANCE The development of antifungal drugs is an urgent task, but it has proven to be difficult due to many similarities between fungal and animal cells. Here, we characterized the urease system in A. fumigatus, which depends on nickel for activity. Notably, nickel is not a crucial element for humans. Therefore, we went further to explore the role of nickel-dependent urease in host-pathogen interactions. We were able to show that urease is important in preventing the acidification of the phagosome and therefore reduces the killing of conidia by macrophages. Furthermore, the deletion of urease shows reduced virulence in murine infection models. Taken together, we identified urease as an essential virulence factor of A. fumigatus. We were able to show that the application of the nickel-chelator dimethylglyoxime is effective in both in vitro and in vivo infection models. This suggests that nickel chelators or urease inhibitors are potential candidates for the development of novel antifungal drugs.
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spelling pubmed-101008642023-04-14 Urease of Aspergillus fumigatus Is Required for Survival in Macrophages and Virulence Xiong, Zhenzhen Zhang, Nan Xu, Liru Deng, Zhiduo Limwachiranon, Jarukitt Guo, Yaojie Han, Yi Yang, Wei Scharf, Daniel H. Microbiol Spectr Research Article The number of patients suffering from fungal diseases has constantly increased during the last decade. Among the fungal pathogens, the airborne filamentous fungus Aspergillus fumigatus can cause chronic and fatal invasive mold infections. So far, only three major classes of drugs (polyenes, azoles, and echinocandins) are available for the treatment of life-threatening fungal infections, and all present pharmacological drawbacks (e.g., low solubility or toxicity). Meanwhile, clinical antifungal-resistant isolates are continuously emerging. Therefore, there is a high demand for novel antifungal drugs, preferentially those that act on new targets. We studied urease and the accessory proteins in A. fumigatus to determine their biochemical roles and their influence on virulence. Urease is crucial for the growth on urea as the sole nitrogen source, and the transcript and protein levels are elevated on urea media. The urease deficient mutant displays attenuated virulence, and its spores are more susceptible to macrophage-mediated killing. We demonstrated that this observation is associated with an inability to prevent the acidification of the phagosome. Furthermore, we could show that a nickel-chelator inhibits growth on urea. The nickel chelator is also able to reverse the effects of urease on macrophage killing and phagosome acidification, thereby reducing virulence in systemic and trachea infection models. IMPORTANCE The development of antifungal drugs is an urgent task, but it has proven to be difficult due to many similarities between fungal and animal cells. Here, we characterized the urease system in A. fumigatus, which depends on nickel for activity. Notably, nickel is not a crucial element for humans. Therefore, we went further to explore the role of nickel-dependent urease in host-pathogen interactions. We were able to show that urease is important in preventing the acidification of the phagosome and therefore reduces the killing of conidia by macrophages. Furthermore, the deletion of urease shows reduced virulence in murine infection models. Taken together, we identified urease as an essential virulence factor of A. fumigatus. We were able to show that the application of the nickel-chelator dimethylglyoxime is effective in both in vitro and in vivo infection models. This suggests that nickel chelators or urease inhibitors are potential candidates for the development of novel antifungal drugs. American Society for Microbiology 2023-03-14 /pmc/articles/PMC10100864/ /pubmed/36916906 http://dx.doi.org/10.1128/spectrum.03508-22 Text en Copyright © 2023 Xiong et al. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Research Article
Xiong, Zhenzhen
Zhang, Nan
Xu, Liru
Deng, Zhiduo
Limwachiranon, Jarukitt
Guo, Yaojie
Han, Yi
Yang, Wei
Scharf, Daniel H.
Urease of Aspergillus fumigatus Is Required for Survival in Macrophages and Virulence
title Urease of Aspergillus fumigatus Is Required for Survival in Macrophages and Virulence
title_full Urease of Aspergillus fumigatus Is Required for Survival in Macrophages and Virulence
title_fullStr Urease of Aspergillus fumigatus Is Required for Survival in Macrophages and Virulence
title_full_unstemmed Urease of Aspergillus fumigatus Is Required for Survival in Macrophages and Virulence
title_short Urease of Aspergillus fumigatus Is Required for Survival in Macrophages and Virulence
title_sort urease of aspergillus fumigatus is required for survival in macrophages and virulence
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10100864/
https://www.ncbi.nlm.nih.gov/pubmed/36916906
http://dx.doi.org/10.1128/spectrum.03508-22
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