Genetic Manipulation in Mucorales and New Developments to Study Mucormycosis

Lax, Carlos; Cánovas-Márquez, José Tomás; Tahiri, Ghizlane; Navarro, Eusebio; Garre, Victoriano

doi:10.3390/ijms23073454

Cited by 8 publications

(5 citation statements)

References 109 publications

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“…Regarding the study models, the wide range of genetic tools now available in M. lusitanicus demonstrates that this fungus remains the most suitable study model for the genetic dissection of various cellular processes in Mucorales [ 108 , 109 ]. The current possibilities to manipulate M. lusitanicus include gene deletion, interruption, complementation, overexpression, labeling with fluorescent makers, amino acid substitution, RNAi silencing, and functional genomic libraries [ 110 , 111 ]. More recently, M. lusitanicus has served as a new model to study adenine methylation in eukaryotes [ 112 ].…”

Section: Discussionmentioning

confidence: 99%

Mucorales and Mucormycosis: Recent Insights and Future Prospects

Tahiri

Lax

Cánovas-Márquez

et al. 2023

JoF

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The classification of Mucorales encompasses a collection of basal fungi that have traditionally demonstrated an aversion to modern genetic manipulation techniques. This aversion led to a scarcity of knowledge regarding their biology compared to other fungal groups. However, the emergence of mucormycosis, a fungal disease caused by Mucorales, has attracted the attention of the clinical field, mainly because available therapies are ineffective for decreasing the fatal outcome associated with the disease. This revitalized curiosity about Mucorales and mucormycosis, also encouraged by the recent COVID-19 pandemic, has spurred a significant and productive effort to uncover their mysteries in recent years. Here, we elaborate on the most remarkable breakthroughs related to the recently discovered genetic advances in Mucorales and mucormycosis. The utilization of a few genetic study models has enabled the identification of virulence factors in Mucorales that were previously described in other pathogens. More notably, recent investigations have identified novel genes and mechanisms controlling the pathogenic potential of Mucorales and their interactions with the host, providing fresh avenues to devise new strategies against mucormycosis. Finally, new study models are allowing virulence studies that were previously hampered in Mucorales, predicting a prolific future for the field.

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Section: Discussionmentioning

confidence: 99%

Mucorales and Mucormycosis: Recent Insights and Future Prospects

Tahiri

Lax

Cánovas-Márquez

et al. 2023

JoF

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“…Deciphering virulence traits on a genetic level has been delayed in Mucorales due to unavailability of annotated genome sequences and their reluctance to genetic modification. Luckily, this has improved tremendously in the last decade and, although it is still more difficult than in other fungi, great tools and protocols have been established to delete or silence genes ( Lax et al., 2022 ). To decipher the role of these genes for virulence, Galleria larvae have been employed.…”

Section: Invertebrate Modelsmentioning

confidence: 99%

Alternative in-vivo models of mucormycosis

Scheler,

Binder

2024

Front. Cell. Infect. Microbiol.

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Mucormycosis is still regarded a rare fungal infection, but the high incidences of COVID-associated cases in India and other countries have shown its potential threat to large patient cohorts. In addition, infections by these fast-growing fungi are often fatal and cause disfigurement, badly affecting patients’ lives. In advancing our understanding of pathogenicity factors involved in this disease, to enhance the diagnostic toolset and to evaluate novel treatment regimes, animal models are indispensable. As ethical and practical considerations typically favor the use of alternative model systems, this review provides an overview of alternative animal models employed for mucormycosis and discusses advantages and limitations of the respective model.

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“…While tools are evolving to study gene function in some pathogenic moulds, such as Rhizopus microsporus [55] and R. arrhizus [56], Mucor lusitanicus [57] and E. dermatitidis [58], methods are still lacking for the many species in our study. Further, existing methodologies to knock out genes vary greatly in terms of mechanism, reagents and efficiency.…”

Section: Plos Onementioning

confidence: 99%

“…While tools are evolving to study gene function in some pathogenic moulds, such as Rhizopus microsporus [ 55 ] and R . arrhizus [ 56 ], Mucor lusitanicus [ 57 ] and E . dermatitidis [ 58 ], methods are still lacking for the many species in our study.…”

Section: Introductionmentioning

confidence: 99%

Characterisation of putative class 1A DHODH-like proteins from Mucorales and dematiaceous mould species

Pinder¹,

Lebedinec²,

Levine³

et al. 2023

PLoS ONE

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Olorofim is a new antifungal in clinical development which has a novel mechanism of action against dihydroorotate dehydrogenase (DHODH). DHODH form a ubiquitous family of enzymes in the de novo pyrimidine biosynthetic pathway and are split into class 1A, class 1B and class 2. Olorofim specifically targets the fungal class 2 DHODH present in a range of pathogenic moulds. The nature and number of DHODH present in many fungal species have not been addressed for large clades of this kingdom. Mucorales species do not respond to olorofim; previous work suggests they have only class 1A DHODH and so lack the class 2 target that olorofim inhibits. The dematiaceous moulds have mixed susceptibility to olorofim, yet previous analyses imply that they have class 2 DHODH. As this is at odds with their intermediate susceptibility to olorofim, we hypothesised that these pathogens may maintain a second class of DHODH, facilitating pyrimidine biosynthesis in the presence of olorofim. The aim of this study was to investigate the DHODH repertoire of clinically relevant species of Mucorales and dematiaceous moulds to further characterise these pathogens and understand variations in olorofim susceptibility. Using bioinformatic analysis, S. cerevisiae complementation and biochemical assays of recombinant protein, we provide the first evidence that two representative members of the Mucorales have only class 1A DHODH, substantiating a lack of olorofim susceptibility. In contrast, bioinformatic analyses initially suggested that seven dematiaceous species appeared to harbour both class 1A-like and class 2-like DHODH genes. However, further experimental investigation of the putative class 1A-like genes through yeast complementation and biochemical assays characterised them as dihydrouracil oxidases rather than DHODHs. These data demonstrate variation in dematiaceous mould olorofim susceptibility is not due to a secondary DHODH and builds on the growing picture of fungal dihydrouracil oxidases as an example of horizontal gene transfer.

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Genetic Manipulation in Mucorales and New Developments to Study Mucormycosis

Cited by 8 publications

References 109 publications

Mucorales and Mucormycosis: Recent Insights and Future Prospects

Mucorales and Mucormycosis: Recent Insights and Future Prospects

Alternative in-vivo models of mucormycosis

Characterisation of putative class 1A DHODH-like proteins from Mucorales and dematiaceous mould species

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