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Review
. 2020 Sep 16;9(9):754.
doi: 10.3390/pathogens9090754.

Pathogenic Delivery: The Biological Roles of Cryptococcal Extracellular Vesicles

Affiliations
Review

Pathogenic Delivery: The Biological Roles of Cryptococcal Extracellular Vesicles

Haroldo C de Oliveira et al. Pathogens. .

Abstract

Extracellular vesicles (EVs) are produced by all domains of life. In fungi, these structures were first described in Cryptococcus neoformans and, since then, they were characterized in several pathogenic and non-pathogenic fungal species. Cryptococcal EVs participate in the export of virulence factors that directly impact the Cryptococcus-host interaction. Our knowledge of the biogenesis and pathogenic roles of Cryptococcus EVs is still limited, but recent methodological and scientific advances have improved our understanding of how cryptococcal EVs participate in both physiological and pathogenic events. In this review, we will discuss the importance of cryptococcal EVs, including early historical studies suggesting their existence in Cryptococcus, their putative mechanisms of biogenesis, methods of isolation, and possible roles in the interaction with host cells.

Keywords: Cryptococcus spp.; biogenesis; extracellular vesicle analysis; extracellular vesicles.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Main discoveries related to cryptococcal extracellular vesicles (EVs). The timeline herein illustrated for Cryptococcus findings was based on that described for all fungal EVs [28].
Figure 2
Figure 2
EV export and transport of virulence traits in Cryptococcus spp. (I) Vesicle-mediated export of cryptococcal virulence factors are impacted by both conventional (A) and unconventional (B) secretory pathways. (C) Transport of GXM, a major virulence factor that is transported in vesicles, is impacted by both pathways, as illustrated by the need of the SAV1 gene (conventional secretion), and the possible involvement of the VPS27 gene (unconventional secretion) for polysaccharide export. GXM-containing EVs in the outer space might operate as a polysaccharide source for capsule construction. At least two proteins related to membrane architecture and EV formation (Aim25 and Apt1) participate in GXM export. (D) Laccase export is affected by the expression of genes operating in the ESCRT complex (VPS34, VPS27, and HSEI). SEC6, a component of the secretory pathway, also participate in vesicle-mediated melanization. (E) Urease is another virulence factor exported in EVs and its activity is also influenced by genes participating in conventional (SEC6) and unconventional (VPS27) secretory pathways. (F) RNA is also exported in EVs (H) through mechanisms that require CIN1 and GRASP. (G) EVs carrying virulence factors of Cryptococcus may also originate directly from the plasma membrane. However, the molecular mechanisms behind this process are still unknown. (II) Illustration of a cryptococcal EV.
Figure 3
Figure 3
Cryptococcus EVs are biologically active and modulate the activity of immune cells. Cryptococcal EVs containing diverse compounds leave the fungal cell and are incorporated by host phagocytes, where they have a number of modulatory activities. (A) EVs can reach the intracellular space, where their cargo modulates the host response, as illustrated by the increased production of TGF-β and IL-10, and decreased release of TNF-α and nitric oxide (NO). A possible outcome of EV exposure is a defective antifungal response by the macrophages, favoring cryptococcal intracellular replication. (B) Galectin-3 (Gal-3) can interact with EVs and disrupt them, leading to failure in the delivery of concentrated virulence factors into host cells and tissues. (C) Cryptococcal EVs represent a potential vaccine strategy to cryptococcosis. EVs from an acapsular C. neoformans mutant or enriched with sterylglucosides (SGs) favor the survival of mice and G. mellonella after a lethal challenge with C. neoformans, respectively. (D) Cryptococcus EVs also play a role in cell-to-cell communication, turning hypovirulent C. gattii cells into a virulent population.
Figure 4
Figure 4
Protocols to isolate cryptococcal EVs. The upper panel (A) summarizes EV isolation from liquid cultures. The lower panel (B) summarizes the protocol used for EV isolation from agar plates. For details, please visit the references mentioned in panel (A) [4] and (B) [66].

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