The sulfur-related metabolic status of Aspergillus fumigatus during infection reveals cytosolic serine hydroxymethyltransferase as a promising antifungal target
Sulfur metabolism is an essential aspect of fungal physiology and pathogenicity. Fungal sulfur metabolism comprises anabolic and catabolic routes that are not well conserved in mammals, therefore is considered a promising source of prospective novel antifungal targets. To gain insight into Aspergill...
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| Format: | Article |
| Language: | English |
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Taylor & Francis Group
2025-12-01
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| Series: | Virulence |
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| Online Access: | https://www.tandfonline.com/doi/10.1080/21505594.2024.2449075 |
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| author | Reem Alharthi Monica Sueiro-Olivares Isabelle Storer Hajer Bin Shuraym Jennifer Scott Reem Al-Shidhani Rachael Fortune-Grant Elaine Bignell Lydia Tabernero Michael Bromley Can Zhao Jorge Amich |
| author_facet | Reem Alharthi Monica Sueiro-Olivares Isabelle Storer Hajer Bin Shuraym Jennifer Scott Reem Al-Shidhani Rachael Fortune-Grant Elaine Bignell Lydia Tabernero Michael Bromley Can Zhao Jorge Amich |
| author_sort | Reem Alharthi |
| collection | DOAJ |
| description | Sulfur metabolism is an essential aspect of fungal physiology and pathogenicity. Fungal sulfur metabolism comprises anabolic and catabolic routes that are not well conserved in mammals, therefore is considered a promising source of prospective novel antifungal targets. To gain insight into Aspergillus fumigatus sulfur-related metabolism during infection, we used a NanoString custom nCounter-TagSet and compared the expression of 68 key metabolic genes in different murine models of invasive pulmonary aspergillosis, at 3 time-points, and under a variety of in vitro conditions. We identified a set of 15 genes that were consistently expressed at higher levels in vivo than in vitro, suggesting that they may be particularly relevant for intrapulmonary growth and thus constitute promising drug targets. Indeed, the role of 5 of the 15 genes has previously been empirically validated, supporting the likelihood that the remaining candidates are relevant. In addition, the analysis of gene expression dynamics at early (16 h), mid (24 h), and late (72 h) time-points uncovered potential disease initiation and progression factors. We further characterized one of the identified genes, encoding the cytosolic serine hydroxymethyltransferase ShmB, and demonstrated that it is an essential gene of A. fumigatus, also required for virulence in a murine model of established pulmonary infection. We further showed that the structure of the ligand-binding pocket of the fungal enzyme differs significantly from its human counterpart, suggesting that specific inhibitors can be designed. Therefore, in vivo transcriptomics is a powerful tool for identifying genes crucial for fungal pathogenicity that may encode promising antifungal target candidates. |
| format | Article |
| id | doaj-art-2989e49dff784c7a8c5c8d67af8797e7 |
| institution | Kabale University |
| issn | 2150-5594 2150-5608 |
| language | English |
| publishDate | 2025-12-01 |
| publisher | Taylor & Francis Group |
| record_format | Article |
| series | Virulence |
| spelling | doaj-art-2989e49dff784c7a8c5c8d67af8797e72025-01-18T07:08:23ZengTaylor & Francis GroupVirulence2150-55942150-56082025-12-0116110.1080/21505594.2024.2449075The sulfur-related metabolic status of Aspergillus fumigatus during infection reveals cytosolic serine hydroxymethyltransferase as a promising antifungal targetReem Alharthi0Monica Sueiro-Olivares1Isabelle Storer2Hajer Bin Shuraym3Jennifer Scott4Reem Al-Shidhani5Rachael Fortune-Grant6Elaine Bignell7Lydia Tabernero8Michael Bromley9Can Zhao10Jorge Amich11Manchester Fungal Infection Group (MFIG), Division of Evolution, Infection, and Genomics, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UKManchester Fungal Infection Group (MFIG), Division of Evolution, Infection, and Genomics, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UKManchester Fungal Infection Group (MFIG), Division of Evolution, Infection, and Genomics, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UKManchester Fungal Infection Group (MFIG), Division of Evolution, Infection, and Genomics, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UKManchester Fungal Infection Group (MFIG), Division of Evolution, Infection, and Genomics, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UKLydia Becker Institute for Immunology and Inflammation, School of Biological Sciences, Faculty of Biology Medicine and Health, Manchester Academic Health Science Centre, University of Manchester, Manchester, UKManchester Fungal Infection Group (MFIG), Division of Evolution, Infection, and Genomics, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UKMRC Centre for Medical Mycology, University of Exeter, Exeter, UKLydia Becker Institute for Immunology and Inflammation, School of Biological Sciences, Faculty of Biology Medicine and Health, Manchester Academic Health Science Centre, University of Manchester, Manchester, UKManchester Fungal Infection Group (MFIG), Division of Evolution, Infection, and Genomics, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UKDepartment of Life Sciences, Manchester Metropolitan University, Manchester, UKManchester Fungal Infection Group (MFIG), Division of Evolution, Infection, and Genomics, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UKSulfur metabolism is an essential aspect of fungal physiology and pathogenicity. Fungal sulfur metabolism comprises anabolic and catabolic routes that are not well conserved in mammals, therefore is considered a promising source of prospective novel antifungal targets. To gain insight into Aspergillus fumigatus sulfur-related metabolism during infection, we used a NanoString custom nCounter-TagSet and compared the expression of 68 key metabolic genes in different murine models of invasive pulmonary aspergillosis, at 3 time-points, and under a variety of in vitro conditions. We identified a set of 15 genes that were consistently expressed at higher levels in vivo than in vitro, suggesting that they may be particularly relevant for intrapulmonary growth and thus constitute promising drug targets. Indeed, the role of 5 of the 15 genes has previously been empirically validated, supporting the likelihood that the remaining candidates are relevant. In addition, the analysis of gene expression dynamics at early (16 h), mid (24 h), and late (72 h) time-points uncovered potential disease initiation and progression factors. We further characterized one of the identified genes, encoding the cytosolic serine hydroxymethyltransferase ShmB, and demonstrated that it is an essential gene of A. fumigatus, also required for virulence in a murine model of established pulmonary infection. We further showed that the structure of the ligand-binding pocket of the fungal enzyme differs significantly from its human counterpart, suggesting that specific inhibitors can be designed. Therefore, in vivo transcriptomics is a powerful tool for identifying genes crucial for fungal pathogenicity that may encode promising antifungal target candidates.https://www.tandfonline.com/doi/10.1080/21505594.2024.2449075Aspergillus fumigatussulfur metabolismantifungal targetsin vivo transcriptomicsfungal virulencehydroxymethyltransferase |
| spellingShingle | Reem Alharthi Monica Sueiro-Olivares Isabelle Storer Hajer Bin Shuraym Jennifer Scott Reem Al-Shidhani Rachael Fortune-Grant Elaine Bignell Lydia Tabernero Michael Bromley Can Zhao Jorge Amich The sulfur-related metabolic status of Aspergillus fumigatus during infection reveals cytosolic serine hydroxymethyltransferase as a promising antifungal target Virulence Aspergillus fumigatus sulfur metabolism antifungal targets in vivo transcriptomics fungal virulence hydroxymethyltransferase |
| title | The sulfur-related metabolic status of Aspergillus fumigatus during infection reveals cytosolic serine hydroxymethyltransferase as a promising antifungal target |
| title_full | The sulfur-related metabolic status of Aspergillus fumigatus during infection reveals cytosolic serine hydroxymethyltransferase as a promising antifungal target |
| title_fullStr | The sulfur-related metabolic status of Aspergillus fumigatus during infection reveals cytosolic serine hydroxymethyltransferase as a promising antifungal target |
| title_full_unstemmed | The sulfur-related metabolic status of Aspergillus fumigatus during infection reveals cytosolic serine hydroxymethyltransferase as a promising antifungal target |
| title_short | The sulfur-related metabolic status of Aspergillus fumigatus during infection reveals cytosolic serine hydroxymethyltransferase as a promising antifungal target |
| title_sort | sulfur related metabolic status of aspergillus fumigatus during infection reveals cytosolic serine hydroxymethyltransferase as a promising antifungal target |
| topic | Aspergillus fumigatus sulfur metabolism antifungal targets in vivo transcriptomics fungal virulence hydroxymethyltransferase |
| url | https://www.tandfonline.com/doi/10.1080/21505594.2024.2449075 |
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