Genes, Pathways, and Mechanisms Involved in the Virulence of Mucorales

Abstract

The order Mucorales is a group of ancient fungi with limited tools for gene manipulation. The main consequence of this manipulation unwillingness is the limited knowledge about its biology compared to other fungal groups. However, the emerging of mucormycosis, a fungal infection caused by Mucorales, is attracting the medical spotlight in recent years because the treatments available are not efficient in reducing the high mortality associated with this disease. The result of this renewed interest in Mucorales and mucormycosis is an extraordinarily productive effort to unveil their secrets during the last decade. In this review, we describe the most compelling advances related to the genetic study of virulence factors, pathways, and molecular mechanisms developed in these years. The use of a few genetic study models has allowed the characterization of virulence factors in Mucorales that were previously described in other pathogens, such as the uptake iron systems, the mechanisms of dimorphism, and azole resistances. More importantly, recent studies are identifying new genes and mechanisms controlling the pathogenic potential of Mucorales and their interactions with the host, offering new alternatives to develop specific strategies against mucormycosis.Genes 2020, 11, 317 2 of 17 Mucorales are a neglected phylogenetic group compared to others such as Ascomycetes and Basidiomycetes. The limited knowledge about the genetics of Mucorales is a consequence of the restricted tools for gene manipulation, as most of them cannot be transformed. However, DNA can be introduced in Mucor circinelloides, Rhizopus delemar, and Rhizopus oryzae [6,7]. These genetic models and the alarm raised for the emerging cases of mucormycosis are attracting the interest of the scientific community. Thus, the last decade has produced several studies related to genes, pathways, and mechanisms showing a direct connection with virulence in Mucorales [8,9]. One of the most studied mechanisms has been the process of gene silencing or RNA interfering (RNAi) in M. circinelloides [10]. After the dissection of the gene silencing machinery, the knowledge of this mechanism allowed the unveiling of a new and particular type of antifungal resistance mediated by temporal epigenetic changes [11]. In addition, the applied use of gene silencing enabled the development of functional genomics techniques, which have been used for the identification of several new virulence factors [12]. Along with silencing, gene disruption driven by homologous recombination has also allowed the study of the particular role in M. circinelloides of virulence factors identified in other fungi, such as the role of a high-affinity iron uptake mechanism, the protein family of CotH, and the calcineurin pathway. Moreover, the implementation of the new omics technologies has produced a long list of candidate genes not previously related to virulence, becoming promising targets for the development of new treatments against mucormycosis. Finally, the diversity of molecular and cell methodolo...

Iron Assimilation during Emerging Infections Caused by Opportunistic Fungi with emphasis on Mucorales and the Development of Antifungal Resistance

“…Grp78/HspA5 is overexpressed in patients with hyperglycaemia, DKA, and elevated serum iron; thus, antibodies, i.e., anti-Grp78 may be promising novel targets as it was shown to offer protection in a murine DKA model. Similar protective attributes were seen when antibodies of the fungal spore coat protein H or CotH i.e., anti-CotH (the interaction partner of Grp78/HspA5) were used in DKA murine model [105,231,247].…”

“…In mucormycosis, the lipid formulations of AMB, i.e., LAMB and AMB lipid complex, (AMLC) is the optimal treatment option [199,202,204,222,228,230]. It is important to note that Mucoralean fungi are innately resistant to most antifungals in vitro, including voriconazole [231]. Most recently, posaconazole and isavuconazole have exhibited activity against Mucorales [228,231,232].…”

“…It is important to note that Mucoralean fungi are innately resistant to most antifungals in vitro, including voriconazole [231]. Most recently, posaconazole and isavuconazole have exhibited activity against Mucorales [228,231,232].…”

The Evolutionary Significance of RNAi in the Fungal Kingdom

“…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 ].…”

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

“…The virulence potential of a pathogenic organism is a complex process relying on multiple mechanisms and gene pathways [46,47]. The white collar-1 genes control different and diverse pathways and physiological processes, and among them, virulence has been recently identified as a WC-dependent feature in pathogenic fungi.…”