Fungal Extracellular Vesicles: History
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Contributor:
Stefano Nenciarini
,
Duccio Cavalieri

Extracellular vesicles (EVs) are membranous vesicular organelles that perform a variety of biological functions including cell communication across different biological kingdoms. EVs of mammals and, to a lesser extent, bacteria have been deeply studied over the years, whereas investigations of fungal EVs are still in their infancy. Fungi, encompassing both yeast and filamentous forms, are increasingly recognized for their production of extracellular vesicles (EVs) containing a wealth of proteins, lipids, and nucleic acids. These EVs play pivotal roles in orchestrating fungal communities, bolstering pathogenicity, and mediating interactions with the environment. 

  • extracellular vesicles
  • fungi

1. Introduction

Extracellular vesicles (EVs) are defined as cup-sized nanostructures delimited by lipid bilayers [1]. The International Society for Extracellular Vesicles (ISEV) proposed classifying EVs based on their sedimentation speed [2], but most scientists and authors still use a former classification based on the origin and size of EVs, dividing them into exosomes and microvesicles (also called microparticles or ectosomes), which are shared across almost all domains of life [3], and apoptotic bodies, whose presence in fungi is currently under investigation [4]. The debate regarding EV classification is also still unresolved because there is not a universal consensus upon the most reliable methods of isolation, purification and characterisation [5][6][7][8][9][10]. The content of EVs can be very heterogeneous, and mainly includes proteins, lipids and nucleic material [11].
Since their early descriptions as “clotting factors” [12] or “platelet dust” [13], researchers' knowledge on extracellular vesicles (EVs) has tremendously expanded, such that they are currently used in biotechnological, diagnostic and therapeutic applications [14][15][16]. However, several aspects of EVs, such as biogenesis, cargo and releasing mechanisms differ among species and are still far from being wholly understood [17]. Fungal EVs are a recent research field, since they were properly identified for the first time in 2007 in Cryptococcus neoformans [18]. Thanks to their cargo, EVs are used by fungal species to modulate a series of different functions within the fungal community [19]. For instance, they participate in intercellular communication during biofilm formation [20][21], regulate the intracellular proliferation of a population [22], play a critical role in cell wall remodelling [23] and could even mediate the vertical and horizontal transfer of prion-like protein in fungi [24]. In addition to all the intra-kingdom functions, fungal EVs are known to help releasing cells during their interactions with other organisms, such as other fungi and bacteria, or with the host, including animals and plants [4][25]. The interactions between fungi and their host through fungal EVs have been studied especially during infections in mammalian cells, where fungal EVs can exacerbate or attenuate fungal infection by enhancing pathogenicity or modulating virulence strategies [2][26][27][28]. Fungal EVs show the capacity to enter host cells and start a process that can lead to the modulation of antimicrobial activities and immune responses. Several studies investigated the effects of EVs from pathogenic fungi on murine and human immune cells, including macrophages [29][30], keratinocytes [31], dendritic cells (DCs) [32] and neutrophils [33]. These interactions lead to the activation of the innate immune system, but also of the priming activity of T cells through several mechanisms, including the production of pro-inflammatory and anti-inflammatory cytokines.
In addition to fungi, the bigger portion of the literature about the interactions between microbial EVs and the host immune system relies on bacteria. In the last twenty years, there has been a great number of studies regarding EVs both from pathogens [34] and commensal bacteria [35]. Several Gram-negative commensals have been investigated [36][37], while Gram-positive studies have focused on probiotics of the genera Lactobacillus and Bifidobacterium [38][39]. Research on EVs in Gram-positive bacteria, mycobacteria and fungi was neglected until recently, due the presumption that vesicles could not traverse the thick cell walls found in these organisms [40]. Despite the later discovery, EVs from these microorganisms are now comprehensively studied, and share common features, including the delivery of multiple virulence factors that elicit strong immune responses in the host [41].
The current available information on the applications of EVs in drug delivery provides significant groundwork for their development as delivery vehicles to harness their potential for future therapeutic applications. Fungal EVs could represent novel biotechnological tools for diagnostics and immunotherapy. Fungal EVs have been shown to possess most of the characteristics for an ideal vaccine, such as nanometric sizes, being g naturally carriers of multiple antigens, and conjugation with sugars, which can contribute to cell recognition [42].
The increased number of immunocompromised patients [43], and the spread of new fungal pathogens due to environmental and climate change [44][45][46] have significantly modified the rate of fungal infections among humans around the globe, as attested by the Global Action Fund for Fungal Infections (GAFFI) [47][48]. These dramatic data, together with the low efficacy of currently approved antifungal drugs and the outbreak of resistant fungal strains [49][50][51], outline the urgent need for new strategies to both prevent and fight fungal infections.

2. Fungal Fungal Extracellular Vesicles

Fungal EVs have been described in more than twenty different species [19], and it is now assumed that they represent a universal mechanism for the transport of molecules outside the fungal cell [52][53]. 

2.1. Discovery and Seminal Studies

The biological entities that would later be named extracellular vesicles were first described in 1946 by Chargaff and West, who were working on blood coagulation [12]. Only in 1967 did another study by Wolf describe them as platelet-derived material [13]. In fungi, the term “extracellular vesicles” was used for the first time in 1977, in a study on Candida tropicalis [54]. Before that, both Gibson and Peberdy in 1972 [55] and Takeo and colleagues in 1973 [56] reported the presence of outer membranous particles in Aspergillus nidulans and Cryptococcus neoformans, respectively. Despite the fact that in 1990 Anderson and colleagues found wall-crossing vesicles in Candida albicans [57], all of the aforementioned studies did not promote research on fungal EVs, mostly because the thick cell wall of fungi seemed to preclude the production of vesicles destined to the extracellular space [40]. The first set of experimental evidence suggesting the production of EVs by fungi was carried out at the end of the last century, when an attempt to develop monoclonal antibodies against Cryptococcus neoformans was made by Arturo Casadevall, as reported in the footnote of the first book on fungal EVs [58]. Since lipid structures were found in the fungal cell wall, Rodrigues and Nimrichter hypothesised the presence of hydrophobic structures that could reach the cell wall [59]. Following this hypothesis, in 2007 Rodrigues and colleagues isolated EVs from C. neoformans cultures [18], and right after this they demonstrated that these vesicles contain glucuronoxylomannan (GXM), which is the major virulence factor of C. neoformans [60]. Around the same period, Vallejo and colleagues showed that EV production occurs in Paracoccidioides brasiliensis [61]. To date, EVs have been found in more than 20 fungal species, in both yeast-like and filamentous forms, such that the production of EVs is now assumed to be a communication mechanism shared by the whole fungal kingdom. An almost complete list of these species can be found in previous comprehensive reviews [4][19], except (as far as researchers know) for the pathogenic yeast Candida auris, whose EVs have been characterised in the last year [62][63][64]. Fungal EVs have been investigated mostly in human infections and, more generally, in the context of interactions with the human host. Nonetheless, fungal EVs have been studied also regarding their functions in parasitic or mutualistic relationships with plants [25][65][66], defence from predators [67], cell wall synthesis [68] and remodelling [23][61][69], and other physiological roles within fungal communities [70], including morphological transitions during biofilm formation [20][21], the regulation of protein cargo related to nutrients [71][72][73][74] and adaptation to the matrix [75][76][77].

2.2. Biogenesis and Release of Fungal EVs

Despite the fact that studies on the production of fungal EVs have been conducted for more than a decade, the mechanisms of their biogenesis are still unknown. Nevertheless, proteomic, genetic and in silico analyses have provided insights into certain molecular patterns related to EV trafficking, which are already extensively discussed elsewhere [4][19][27][78][79][80][81].
Mammalian vesicles, which have been far more frequently investigated than fungal ones have, are finely classified in different subpopulations, depending on the size and origin [82][83][84][85]. Currently, studies on fungal EVs also divide them into exosomes, which correspond roughly to small EVs in the ISEV classification and are smaller than 150 nm, and microvesicles, which correspond to medium EVs and are larger than 150 nm [27]. The most important difference between exosomes and microvesicles, apart from size, is the mechanism of biogenesis. Exosomes derive from the endosomal pathway, through the formation of multivesicular bodies (MVBs) which contain several vesicles. They fuse with the plasma membrane releasing them into the intraluminal space. On the other hand, microvesicles (or ectosomes) originate directly from projections of the plasma membrane [78].
Exosome biogenesis, release and cargo selection have been shown to be related with both conventional and unconventional secretory pathways, thanks to genetic deletions, but none of the studied mutations were able to completely cease EV production, suggesting a co-occurrence of the multiple known pathways or the presence of currently unknown ones. Firstly, mutations in SEC genes, which play a role in the post-Golgi conventional secretion pathway, cause an accumulation of vesicles in the cytoplasm [86][87] or vesicles of altered diameters [88] in S. cerevisiae, and a lack of EV detection in C. neoformans [89]. Regarding the unconventional secretion pathways, the most important regulators of EVs production known so far are involved in MVB formation and release. Specifically, a lack of expression of Golgi reassembly and stacking protein (GRASP) causes a reduction in EV release in S. cerevisiae [88] and different EV sizes in C. neoformans [90]. Moreover, a class of proteins of vacuolar protein sorting (VPS) named E-VPS is crucial in the endosomal sorting complexes required for transport (ESCRT) machinery [91][92][93], which coordinate MVB release [94]. Therefore, it has been shown that the deletion of different VPS genes strongly affects the biogenesis of EVs in S. cerevisiae [23][88], C. neoformans [95][96][97][98] and C. albicans [21][99].
The production and release of microvesicles via the invagination of the plasma membrane was shown two decades ago [59], together with observations of cytoplasmic volume loss [88] and cytoplasmic proteins in fungal EVs [100]. Moreover, mutations in genes involved in the composition of the plasma membrane affect EV formation and content [76][101][102][103]. 
Another fungal EV-related process that still needs to be fully understood is cell wall crossing. The fungal cell wall is composed of a core set of molecules that are conserved across the fungal kingdom, mainly beta-glucans, mannoproteins and chitin [104], and of components that are species-specific, such that the wall is probably the part of the cell that exhibits the most diversity and plasticity [105]. Fungal cell walls are nowadays considered dynamic structures whose compositions and pores’ dimensions are highly regulated via environmental conditions [106][107]. Despite this, they have been shown to act as barriers to the passage of EVs, since mutations in cell wall-remodelling genes increase their release [23][98], and an increase in their thickness can lead to an accumulation of vesicles in the area between the plasma membrane and cell wall [108]. Moreover, it still remains poorly understood how vesicles as large as almost 1 μm could pass through these dense polysaccharide/protein matrices. Three nonexclusive hypotheses, already reviewed elsewhere [40][106], are currently under investigation: (i) vesicles can pass the cell wall through guide channels; (ii) there are specific enzymes that could open areas in the wall; (iii) turgor pressure and/or other physical forces could force the passage of EVs through cell wall pores. The last hypothesis has received support via a recent study which demonstrated that the cell wall has viscoelastic properties, which could allow the passage of EVs [109]. However, since that study utilised small liposomes (60–80 nm), the full explanation for the passage of EVs with a broad spectrum of sizes has yet to be found.

2.3. Composition of Fungal EVs

The process of the production and release of EVs is conserved across kingdoms even if it has a considerable energetic cost for the cell, and the reason for that has to be found in the multiple advantages of vesicle packaging compared to soluble secretion directly to the extracellular milieu. Firstly, vesicles protect easily degradable molecules, such as RNAs. Secondly, loading molecules into a confined space prevents the loss of them. Finally, the vesicle co-transportation of more molecules enables their synergistic effect over distances [110]. As stated before, a large part of the knowledge on fungal EVs is derived from studies on mammals, since there are several resemblances between them, including their content in terms of classes of molecules [106]. The most abundant molecules packed the into EVs of both mammals and fungi belong to proteins, lipids and nucleic acids, even though there are other molecules specific to fungi, such as prions. 

2.3.1. Proteins

Proteomic studies on fungal EVs showed a common set of proteins between different species, such as those involved in the stress response, oxidation, metabolic pathways, transport and signalling, while others have proven to be species-specific [53][110][111].
EVs from pathogenic species carry proteins associated with virulence. In C. neoformans, laccases, ureases, phosphatases and heat shock proteins were found [60]; in Paracoccidioides brasiliensis, phosphatases [111]; in Histoplasma capsulatum, catalases, superoxide dismutases and cell-wall hydrolyzing enzymes [69]; in Malassezia sympodialis, multiple allergens [112]; and in C. albicans, numerous proteins related mainly to pathogenesis, cell organisation and the response to stress [113][114].
The protein content of non-pathogenic yeast EVs have also been investigated, especially in S. cerevisiae, Torulaspora delbrueckii, Hanseniaspora uvarum, Candida sake and Metschnikowia pulcherrima [88][115]. Researchers have found proteins implicated in almost every cell pathway, but the most present were heat shock and stress-related proteins, and those involved in cell wall metabolism [116]. Moreover, proteins contained in EVs from Pichia fermentans were shown to be related to dimorphic transition [20].

2.3.2. Lipids

Lipids are the major components of vesicles’ membranes, and also part of their cargo. Several lipids found in fungal EVs have important functions in pathogenesis, biofilm building and membrane formation [110][117][118]. For example, ergosterol, which is commonly found in EVs from all fungal species, is known to be crucial for biofilm building [118]. EVs from C. albicans and C. neoformans are enriched in ergosterol and glucosylceramide [102][114][119], an important immunogenic compound which has been proven to be a good target for inhibiting fungal hyphal formation during pathogenesis [59]. EVs from H. capsulatum and P. brasiliensis were found to mainly contain sterols and phospholipids, such as phosphatidylethanolamine, phosphatidylcholine, and phosphatidylserine, which are key elements in the formation of fungal lipid bilayers [69][117][120].

2.3.3. Nucleic Acids

Concerning nucleic acids, fungal EVs show strong resemblance to those of mammals, transporting several types of both coding and non-coding RNA, which have been compared and reviewed elsewhere [4][121][122][123]. RNAs are receiving special attention in the context of intercellular communication due to the several mechanisms of post-transcriptional regulation, such as those mediated by microRNAs (miRNAs), short interfering RNAs (siRNAs), tRNA-derived fragments (tRFs) and long non-coding RNAs (lncRNAs) [124][125]. However, they are commonly found in EVs across all biological kingdoms [25][126][127][128]. For instance, several studies showed cross-kingdom interactions between fungi and plants through RNA-containing EVs. Pathogen-induced gene silencing (PIGS) is a mechanism of RNAi used by several fungal pathogens [125], such as Botrytis cinerea [129], Verticillium dahliae [130], Puccinia striiformis f.sp. tritici [131] and Fusarium graminearum [132].
Apart from studies on plants, several studies were conducted on yeast species related to humans. The first one was a comparison between the RNA content of five different species, as reported by Da Silva and colleagues in 2015 [133]. These authors found that the most common shared small RNA classes in EVs belong to small nucleolar RNAs (snoRNAs), small nuclear RNA (snRNAs) and tRNA-derived fragments (tRFs). Then, EVs from Malassezia sympodialis were shown to contain small RNAs similar to miRNAs [134], which was also the case in Pichia fermentans [20], while Histoplasma capsulatum EVs contained 25 nt long anti-sense RNAs [135]. Moreover, a few studies have indicated that the EV-RNA composition differs from the cellular composition [90][136]. The RNA content of EVs from P. brasiliensis and P. lutzii shared mRNA sequences related to protein modification and DNA metabolism, as well as small non-coding RNAs, some of which could potentially modulate the murine immune response [137]. A study on Cryptococcus gattii focused on the impact of the membrane architecture on the formation and content of EVs revealed that the RNA cargo was strongly altered in mutant cells [76]. Finally, a recent study comparing the EV cargos and functions of Candida albicans, a human-related yeast, and Candida auris, a new fungal pathogen that has emerged as a result of global warming [45], found significant differences in RNA content and speculated that these differences could explain the phenotypic changes induced by these EVs in human cells during immunological assays [62].

2.3.4. Other Molecules

Other than proteins, lipids and nucleic acids, the most abundant molecules found in fungal EVs are carbohydrates, pigments and prions. Glucuronoxylomannan (GXM) has been found in EVs from C. neoformans [18], and in C. gattii [76][138]. Moreover, other polysaccharides have been found in EVs from P. brasiliensis [61], P. lutzii [139] and C. albicans [21]. C. neoformans EVs were also found to carry melanin in an older study [140]. Prions have been found in EVs from S. cerevisiae, both in soluble and aggregated forms [24][141], and it has been hypothesised that they can play a role in vertical and horizontal transmission [142].

This entry is adapted from the peer-reviewed paper 10.3390/biom13101487

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