Extracellular Vesicles From the Dermatophyte Trichophyton interdigitale Modulate Macrophage and Keratinocyte Functions

Abstract

The release of biomolecules critically affects all pathogens and their establishment of diseases. For the export of several biomolecules in diverse species, the use of extracellular vesicles (EVs) is considered to represent an alternative transport mechanism, but no study to date has investigated EVs from dermatophytes. Here, we describe biologically active EVs from the dermatophyte Trichophyton interdigitale, a causative agent of mycoses worldwide. EV preparations from T. interdigitale were examined using nanoparticle-tracking analysis, which revealed vesicular structures 20–380 nm in diameter. These vesicles induced the production of proinflammatory mediators by bone marrow-derived macrophages (BMDMs) and keratinocytes in a dose-dependent manner, and an addition of the EVs to BMDMs also stimulated the transcription of the M1-polarization marker iNOS (inducible nitric oxide synthase) and diminished the expression of the M2 markers arginase-1 and Ym-1. The observed M1 macrophages' polarization triggered by EVs was abolished in cells obtained from knockout Toll-like receptor-2 mice. Also, the EVs-induced productions of pro-inflammatory mediators were blocked too. Furthermore, the EVs from T. interdigitale enhanced the fungicidal activity of BMDMs. These results suggest that EVs from T. interdigitale can modulate the innate immune response of the host and influence the interaction between T. interdigitale and host immune cells. Our findings thus open new areas of investigation into the host-parasite relationship in dermatophytosis.

Extracellular Vesicles Released From the Skin Commensal Yeast Malassezia sympodialis Activate Human Primary Keratinocytes

“…To unravel the presence and biological significance of different EVs in vivo detailed studies are needed requiring development of new technologies (Coelho and Casadevall, 2019;Margolis and Sadovsky, 2019). In agreement with our observation that keratinocytes can be activated by fungal EVs in vitro is a study where EVs from the dermatophyte Trichophyton interdigitale induced the release of proinflammatory mediators by the human keratinocyte line HaCat after 24 co-culture (Bitencourt et al, 2018). Recently, EVs from Malassezia furfur were found capable to stimulate IL-6 production in HaCaT cells and mice epidermal keratinocytes (Zhang et al, 2019), strongly supporting our results that Malassezia EVs, not only their parental whole yeast cells (Watanabe et al, 2001;Ishibashi et al, 2006;Donnarumma et al, 2014), have the capacity to activate keratinocytes.…”

Extracellular vesicles from the apoplastic fungal wheat pathogen Zymoseptoria tritici

“…Similarly, our proteomic analysis of Z. tritici EVs suggests the protein cargo broadly overlaps with existing fungal EVs proteomes, given the majority of proteins identi ed shared orthogroups with EV proteins from more than one fungal species. This observation, combined with the fact that the presence of EV particles appears reduced in heat-treated Z. tritici cultures -a result seen in other fungi [28,42,43] -consolidates the hypothesis that Z. tritici EVs are actively secreted by cells rather than being randomly-shed membranous artefacts [44]. To this end, Z. tritici EVs also contain some proteins consistently associated with mammalian EVs, including the cytoskeletal components actin and tubulin; proteins implicated in signal transduction such as 14-3-3 domain-containing proteins; clathrin, which is involved in mammalian EV biogenesis as well as clathrin-mediated endocytosis; and heat-shock proteins, including Hsp70 family and Hsp90 proteins [21,45,46].…”

Fungal Extracellular Vesicles with a Focus on Proteomic Analysis

“…T. interdigitale is one of the major causative agents of dermatophytosis . Similar to P. brasiliensis , T. interdigitale EVs promote M1 polarization of murine macrophages and stimulate the release of pro‐inflammatory cytokines such as TNF‐α, IL‐6, and IL‐1β, which is dependent on Toll‐like receptor 2 . These EVs also activate keratinocytes which produce a similar pro‐inflammatory response, and promote the fungicidal activity of macrophages .…”