Mucorales Species and Macrophages

Nicolás, Francisco E.; Murcia, Laura; Navarro, Eusebio; Navarro-Mendoza, María Isabel; Pérez-Arques, Carlos

doi:10.3390/jof6020094

Cited by 57 publications

(47 citation statements)

References 70 publications

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“…The second condition was a co-culture of spores and the J774A.1 cell-line of mouse macrophages (1.5:1 spore–macrophage ratio) for 5 h, ensuring the phagocytosis of all the spores. This second condition is a novel study model in Mucorales to investigate the initial step of fungal infections, in which the pathogen must overcome the innate immune response to continuing the infection and tissue invasion [ 1 ]. The scatter plots of gene expression values in the two conditions described above ( Figure 2 A,B) reveal that the mcwc-1a Δ mutant had significantly different profiles in the two growth conditions.…”

Section: Resultsmentioning

confidence: 99%

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A Mucoralean White Collar-1 Photoreceptor Controls Virulence by Regulating an Intricate Gene Network during Host Interactions

et al. 2021

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Mucolares are an ancient group of fungi encompassing the causal agents for the lethal infection mucormycosis. The high lethality rates, the emerging character of this disease, and the broad antifungal resistance of its causal agents are mucormycosis features that are alarming clinicians and researchers. Thus, the research field around mucormycosis is currently focused on finding specific weaknesses and targets in Mucorales for developing new treatments. In this work, we tested the role of the white-collar genes family in the virulence potential of Mucor lusitanicus. Study of the three genes of this family, mcwc-1a, mcwc-1b, and mcwc-1c, resulted in a marked functional specialization, as only mcwc-1a was essential to maintain the virulence potential of M. lusitanicus. The traditional role of wc-1 genes regulating light-dependent responses is a thoroughly studied field, whereas their role in virulence remains uncharacterized. In this work, we investigated the mechanism involving mcwc-1a in virulence from an integrated transcriptomic and functional approach during the host–pathogen interaction. Our results revealed mcwc-1a as a master regulator controlling an extensive gene network. Further dissection of this gene network clustering its components by type of regulation and functional criteria disclosed a multifunctional mechanism depending on diverse pathways. In the absence of phagocytic cells, mcwc-1a controlled pathways related to cell motility and the cytoskeleton that could be associated with the essential tropism during tissue invasion. After phagocytosis, several oxidative response pathways dependent on mcwc-1a were activated during the germination of M. lusitanicus spores inside phagocytic cells, which is the first stage of the infection. The third relevant group of genes involved in virulence and regulated by mcwc-1a belonged to the “unknown function,” indicating that new and hidden pathways are involved in virulence. The unknown function category is especially pertinent in the study of mucormycosis, as it is highly enriched in specific fungal genes that represent the most promising targets for developing new antifungal compounds. These results unveil a complex multifunctional mechanism used by wc-1 genes to regulate the pathogenic potential in Mucorales that could also apply to other fungal pathogens.

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Section: Resultsmentioning

confidence: 99%

“…Mucormycosis is a threatening infection caused by Mucorales that is the most unexplored host–pathogen interaction [ 1 ]. The recent interest in mucormycosis relies on the three main features of this infection: high mortality rates, its emerging character, and its unusual antifungal resistance.…”

Section: Introductionmentioning

confidence: 99%

A Mucoralean White Collar-1 Photoreceptor Controls Virulence by Regulating an Intricate Gene Network during Host Interactions

et al. 2021

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“…The second condition was a co-culture of spores and the J774A.1 cell-line of mouse macrophages (1.5:1 spore-macrophage ratio) for 5 hours, ensuring the phagocytosis of all the spores. This second condition is a novel study model in Mucorales to investigate the initial step of fungal infections, in which the pathogen must overcome the innate immune response to continuing the infection and tissue invasion [49]. The scatter plots of gene expression values in the two conditions described above ( Figure 2, A and B) revealed that the mcwc-1aΔ mutant had highly significant different profiles in the two growth conditions.…”

Section: A High-throughput Transcriptomic Analysis Reveals the Gene-nmentioning

confidence: 99%

A Mucoralean White Collar-1 Photoreceptor Controls Virulence by Regulating an Intricate Gene-Network during Host Interactions.

Arques¹,

Mendoza²,

Murcia³

et al. 2020

Preprint

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Mucolares are an ancient group of fungi encompassing the causal agents for the lethal infection mucormycosis. The high lethality rates, the emerging character of this disease, and the broad antifungal resistance of its causal agents are mucormycosis features alarming clinicians and researchers. Thus, the research field around mucormycosis is currently focused on finding specific weaknesses and targets in Mucorales for developing new treatments against mucormycosis. In this work, we tested the role of the white-collar genes family in the virulence potential of Mucor lusitanicus. In this regard, the study of the role in virulence of the three genes of this family, mcwc-1a, mcwc-1b, and mcwc-1c, resulted in a marked functional specialization, as only mcwc-1a was essential to maintain the virulence potential of M. lusitanicus. The traditional role of wc-1 genes regulating light-dependent responses is a thoroughly studied field, whereas their role in virulence remains uncharacterized. In this work, we investigated the mechanism involving mcwc-1a in virulence from an integrated transcriptomic and functional approach during the host-pathogen interaction. Our results revealed mcwc-1a as a master regulator controlling an extensive gene-network. Further dissection of this gene-network clustering its components by type of regulation and functional criteria disclosed a multifunctional mechanism depending on diverse pathways. In the absence of phagocytic cells, mcwc-1a controlled pathways related to cell motility and cytoskeleton that could be associated with the essential tropism during tissue invasion. After phagocytosis, several oxidative responding pathways dependent on mcwc-1a were activated during the germination of M. lusitanicus spore inside of phagocytic cells, which is the first stage of the infection. The third relevant group of genes involved in virulence and regulated by mcwc-1a belonged to the “unknown function,” indicating that new and hidden pathways are involved in virulence. The unknown function category is especially pertinent in the study of mucormycosis, as it is highly enriched in specific fungal genes that represent the most promising targets for developing new antifungal compounds. These results essentially unveil a complex multifunctional mechanism used by wc-1 genes to regulate the pathogenic potential in Mucorales that could also apply to other fungal pathogens.

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“…The human pathogenic fungus M. lusitanicus , for instance, shows an intricate RNAi mechanism as a function the interplay of the silencing proteins in three different pathways, named the canonical, epimutational, and noncanonical RNAi pathways. The crosstalk of the RNAi pathways creates a complex network that regulates both basic cellular activities, such as metabolism or vegetative growth, and elaborated mechanisms, including sexual reproduction and pathogenesis [ 23 , 100 , 101 ].…”

Section: Regulation Of Endogenous Genesmentioning

confidence: 99%

“…Additionally, the latest studies established that NCRIP regulates more than 25% of the genome, 3187 genes mostly linked to cellular metabolism, germination, and development, indicating a relevant role in saprophytic growth conditions [ 64 ]. Furthermore, the transcriptomic profile of M. lusitanicus during phagocytosis is similar to that of mutant strains lacking NCRIP [ 64 , 101 ], suggesting that this mechanism is repressing the genetic program of defense against phagocytosis. Thus, the NCRIP also has a relevant role in the pathogenesis of this filamentous fungus (see below for a more detailed description).…”

Section: Regulation Of Endogenous Genesmentioning

confidence: 99%

The Evolutionary Significance of RNAi in the Fungal Kingdom

Lax

Tahiri

Patiño-Medina

et al. 2020

IJMS

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RNA interference (RNAi) was discovered at the end of last millennium, changing the way scientists understood regulation of gene expression. Within the following two decades, a variety of different RNAi mechanisms were found in eukaryotes, reflecting the evolutive diversity that RNAi entails. The essential silencing mechanism consists of an RNase III enzyme called Dicer that cleaves double-stranded RNA (dsRNA) generating small interfering RNAs (siRNAs), a hallmark of RNAi. These siRNAs are loaded into the RNA-induced silencing complex (RISC) triggering the cleavage of complementary messenger RNAs by the Argonaute protein, the main component of the complex. Consequently, the expression of target genes is silenced. This mechanism has been thoroughly studied in fungi due to their proximity to the animal phylum and the conservation of the RNAi mechanism from lower to higher eukaryotes. However, the role and even the presence of RNAi differ across the fungal kingdom, as it has evolved adapting to the particularities and needs of each species. Fungi have exploited RNAi to regulate a variety of cell activities as different as defense against exogenous and potentially harmful DNA, genome integrity, development, drug tolerance, or virulence. This pathway has offered versatility to fungi through evolution, favoring the enormous diversity this kingdom comprises.

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Mucorales Species and Macrophages

Cited by 57 publications

References 70 publications

A Mucoralean White Collar-1 Photoreceptor Controls Virulence by Regulating an Intricate Gene Network during Host Interactions

A Mucoralean White Collar-1 Photoreceptor Controls Virulence by Regulating an Intricate Gene Network during Host Interactions

A Mucoralean White Collar-1 Photoreceptor Controls Virulence by Regulating an Intricate Gene-Network during Host Interactions.

The Evolutionary Significance of RNAi in the Fungal Kingdom

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