Iron regulatory pathways differentially expressed during Madurella mycetomatis grain development in Galleria mellonella

Imad Abugessaisa (), Mickey Konings, Ri-Ichiroh Manabe, Cathal M. Murphy, Tsugumi Kawashima, Akira Hasegawa, Chitose Takahashi, Michihira Tagami, Yasushi Okazaki, Kimberly Eadie, Wilson Lim, Sean Doyle, Annelies Verbon, Ahmed H. Fahal, Takeya Kasukawa and Wendy W. J. van de Sande ()
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Imad Abugessaisa: RIKEN Center for Integrative Medical Sciences
Mickey Konings: Erasmus MC, University Medical Center Rotterdam
Ri-Ichiroh Manabe: RIKEN Center for Integrative Medical Sciences
Cathal M. Murphy: Maynooth University
Tsugumi Kawashima: RIKEN Center for Integrative Medical Sciences
Akira Hasegawa: RIKEN Center for Integrative Medical Sciences
Chitose Takahashi: RIKEN Center for Integrative Medical Sciences
Michihira Tagami: RIKEN Center for Integrative Medical Sciences
Yasushi Okazaki: RIKEN Center for Integrative Medical Sciences
Kimberly Eadie: Erasmus MC, University Medical Center Rotterdam
Wilson Lim: Erasmus MC, University Medical Center Rotterdam
Sean Doyle: Maynooth University
Annelies Verbon: Erasmus MC, University Medical Center Rotterdam
Ahmed H. Fahal: University of Khartoum
Takeya Kasukawa: RIKEN Center for Integrative Medical Sciences
Wendy W. J. van de Sande: Erasmus MC, University Medical Center Rotterdam

Nature Communications, 2025, vol. 16, issue 1, 1-18

Abstract: Abstract Mycetoma is a chronic granulomatous infection of the subcutaneous tissue, most often caused by the fungal pathogen Madurella mycetomatis. Characteristic of the infection is the formation of grains. However, knowledge of the function and formation of the grain is limited. Here, we use a Galleria mellonella larvae infection model and transcriptomic profiling to identify processes associated with M. mycetomatis grain formation. Larvae were infected with M. mycetomatis and, after 4, 24, 72 and 168 h post-inoculation, RNA was extracted from larval content and sequenced. We found that 3498 G. mellonella and 136 M. mycetomatis genes were differentially expressed during infection. In particular, genes encoding proteins related to iron transport were highly expressed by both G. mellonella (transferrin and ferritin) and M. mycetomatis (SidA, SidD and SidI). LC-MS/MS analysis of M. mycetomatis cultured under iron-limiting conditions revealed the presence of SidA and SidD orthologs, and concurrent RP-HPLC and LC-MS identified a singly charged, putative siderophore in culture supernatant. Furthermore, we show that M. mycetomatis can obtain iron from holoferritin. Thus, our results highlight the importance of iron acquisition pathways during grain formation, suggesting potential avenues for development of new diagnostic and therapeutic strategies for mycetoma.

Date: 2025
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DOI: 10.1038/s41467-025-60875-2

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