Human Neutrophils Produce Antifungal Extracellular Vesicles against <named-content content-type="genus-species">Aspergillus fumigatus</named-content>

ABSTRACT Polymorphonuclear granulocytes (PMNs) are indispensable for controlling life-threatening fungal infections. In addition to various effector mechanisms, PMNs also produce extracellular vesicles (EVs). Their contribution to antifungal defense has remained unexplored. We reveal that the clinic...

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Autores principales:	Iordana A. Shopova, Ivan Belyaev, Prasad Dasari, Susanne Jahreis, Maria C. Stroe, Zoltán Cseresnyés, Ann-Kathrin Zimmermann, Anna Medyukhina, Carl-Magnus Svensson, Thomas Krüger, Viktòria Szeifert, Sandor Nietzsche, Theresia Conrad, Matthew G. Blango, Olaf Kniemeyer, Marie von Lilienfeld-Toal, Peter F. Zipfel, Erzsébet Ligeti, Marc Thilo Figge, Axel A. Brakhage
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2020
Materias:	Aspergillus fumigatus azurocidin cathepsin G extracellular vesicle fluorescent image analysis fungi Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/0c73dfd61b2a43bf9cf5f653d3927aec
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spelling	oai:doaj.org-article:0c73dfd61b2a43bf9cf5f653d3927aec2021-11-15T15:57:03ZHuman Neutrophils Produce Antifungal Extracellular Vesicles against <named-content content-type="genus-species">Aspergillus fumigatus</named-content>10.1128/mBio.00596-202150-7511https://doaj.org/article/0c73dfd61b2a43bf9cf5f653d3927aec2020-04-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.00596-20https://doaj.org/toc/2150-7511ABSTRACT Polymorphonuclear granulocytes (PMNs) are indispensable for controlling life-threatening fungal infections. In addition to various effector mechanisms, PMNs also produce extracellular vesicles (EVs). Their contribution to antifungal defense has remained unexplored. We reveal that the clinically important human-pathogenic fungus Aspergillus fumigatus triggers PMNs to release a distinct set of antifungal EVs (afEVs). Proteome analyses indicated that afEVs are enriched in antimicrobial proteins. The cargo and the release kinetics of EVs are modulated by the fungal strain confronted. Tracking of afEVs indicated that they associated with fungal cells and even entered fungal hyphae, resulting in alterations in the morphology of the fungal cell wall and dose-dependent antifungal effects. To assess as a proof of concept whether the antimicrobial proteins found in afEVs might contribute to growth inhibition of hyphae when present in the fungal cytoplasm, two human proteins enriched in afEVs, cathepsin G and azurocidin, were heterologously expressed in fungal hyphae. This led to reduced fungal growth relative to that of a control strain producing the human retinol binding protein 7. In conclusion, extracellular vesicles produced by neutrophils in response to A. fumigatus infection are able to associate with the fungus, limit growth, and elicit cell damage by delivering antifungal cargo. This finding offers an intriguing, previously overlooked mechanism of antifungal defense against A. fumigatus. IMPORTANCE Invasive fungal infections caused by the mold Aspergillus fumigatus are a growing concern in the clinic due to the increasing use of immunosuppressive therapies and increasing antifungal drug resistance. These infections result in high rates of mortality, as treatment and diagnostic options remain limited. In healthy individuals, neutrophilic granulocytes are critical for elimination of A. fumigatus from the host; however, the exact extracellular mechanism of neutrophil-mediated antifungal activity remains unresolved. Here, we present a mode of antifungal defense employed by human neutrophils against A. fumigatus not previously described. We found that extracellular vesicles produced by neutrophils in response to A. fumigatus infection are able to associate with the fungus, limit growth, and elicit cell damage by delivering antifungal cargo. In the end, antifungal extracellular vesicle biology provides a significant step forward in our understanding of A. fumigatus host pathogenesis and opens up novel diagnostic and therapeutic possibilities.Iordana A. ShopovaIvan BelyaevPrasad DasariSusanne JahreisMaria C. StroeZoltán CseresnyésAnn-Kathrin ZimmermannAnna MedyukhinaCarl-Magnus SvenssonThomas KrügerViktòria SzeifertSandor NietzscheTheresia ConradMatthew G. BlangoOlaf KniemeyerMarie von Lilienfeld-ToalPeter F. ZipfelErzsébet LigetiMarc Thilo FiggeAxel A. BrakhageAmerican Society for MicrobiologyarticleAspergillus fumigatusazurocidincathepsin Gextracellular vesiclefluorescent image analysisfungiMicrobiologyQR1-502ENmBio, Vol 11, Iss 2 (2020)
institution	DOAJ
collection	DOAJ
language	EN
topic	Aspergillus fumigatus azurocidin cathepsin G extracellular vesicle fluorescent image analysis fungi Microbiology QR1-502
spellingShingle	Aspergillus fumigatus azurocidin cathepsin G extracellular vesicle fluorescent image analysis fungi Microbiology QR1-502 Iordana A. Shopova Ivan Belyaev Prasad Dasari Susanne Jahreis Maria C. Stroe Zoltán Cseresnyés Ann-Kathrin Zimmermann Anna Medyukhina Carl-Magnus Svensson Thomas Krüger Viktòria Szeifert Sandor Nietzsche Theresia Conrad Matthew G. Blango Olaf Kniemeyer Marie von Lilienfeld-Toal Peter F. Zipfel Erzsébet Ligeti Marc Thilo Figge Axel A. Brakhage Human Neutrophils Produce Antifungal Extracellular Vesicles against <named-content content-type="genus-species">Aspergillus fumigatus</named-content>
description	ABSTRACT Polymorphonuclear granulocytes (PMNs) are indispensable for controlling life-threatening fungal infections. In addition to various effector mechanisms, PMNs also produce extracellular vesicles (EVs). Their contribution to antifungal defense has remained unexplored. We reveal that the clinically important human-pathogenic fungus Aspergillus fumigatus triggers PMNs to release a distinct set of antifungal EVs (afEVs). Proteome analyses indicated that afEVs are enriched in antimicrobial proteins. The cargo and the release kinetics of EVs are modulated by the fungal strain confronted. Tracking of afEVs indicated that they associated with fungal cells and even entered fungal hyphae, resulting in alterations in the morphology of the fungal cell wall and dose-dependent antifungal effects. To assess as a proof of concept whether the antimicrobial proteins found in afEVs might contribute to growth inhibition of hyphae when present in the fungal cytoplasm, two human proteins enriched in afEVs, cathepsin G and azurocidin, were heterologously expressed in fungal hyphae. This led to reduced fungal growth relative to that of a control strain producing the human retinol binding protein 7. In conclusion, extracellular vesicles produced by neutrophils in response to A. fumigatus infection are able to associate with the fungus, limit growth, and elicit cell damage by delivering antifungal cargo. This finding offers an intriguing, previously overlooked mechanism of antifungal defense against A. fumigatus. IMPORTANCE Invasive fungal infections caused by the mold Aspergillus fumigatus are a growing concern in the clinic due to the increasing use of immunosuppressive therapies and increasing antifungal drug resistance. These infections result in high rates of mortality, as treatment and diagnostic options remain limited. In healthy individuals, neutrophilic granulocytes are critical for elimination of A. fumigatus from the host; however, the exact extracellular mechanism of neutrophil-mediated antifungal activity remains unresolved. Here, we present a mode of antifungal defense employed by human neutrophils against A. fumigatus not previously described. We found that extracellular vesicles produced by neutrophils in response to A. fumigatus infection are able to associate with the fungus, limit growth, and elicit cell damage by delivering antifungal cargo. In the end, antifungal extracellular vesicle biology provides a significant step forward in our understanding of A. fumigatus host pathogenesis and opens up novel diagnostic and therapeutic possibilities.
format	article
author	Iordana A. Shopova Ivan Belyaev Prasad Dasari Susanne Jahreis Maria C. Stroe Zoltán Cseresnyés Ann-Kathrin Zimmermann Anna Medyukhina Carl-Magnus Svensson Thomas Krüger Viktòria Szeifert Sandor Nietzsche Theresia Conrad Matthew G. Blango Olaf Kniemeyer Marie von Lilienfeld-Toal Peter F. Zipfel Erzsébet Ligeti Marc Thilo Figge Axel A. Brakhage
author_facet	Iordana A. Shopova Ivan Belyaev Prasad Dasari Susanne Jahreis Maria C. Stroe Zoltán Cseresnyés Ann-Kathrin Zimmermann Anna Medyukhina Carl-Magnus Svensson Thomas Krüger Viktòria Szeifert Sandor Nietzsche Theresia Conrad Matthew G. Blango Olaf Kniemeyer Marie von Lilienfeld-Toal Peter F. Zipfel Erzsébet Ligeti Marc Thilo Figge Axel A. Brakhage
author_sort	Iordana A. Shopova
title	Human Neutrophils Produce Antifungal Extracellular Vesicles against <named-content content-type="genus-species">Aspergillus fumigatus</named-content>
title_short	Human Neutrophils Produce Antifungal Extracellular Vesicles against <named-content content-type="genus-species">Aspergillus fumigatus</named-content>
title_full	Human Neutrophils Produce Antifungal Extracellular Vesicles against <named-content content-type="genus-species">Aspergillus fumigatus</named-content>
title_fullStr	Human Neutrophils Produce Antifungal Extracellular Vesicles against <named-content content-type="genus-species">Aspergillus fumigatus</named-content>
title_full_unstemmed	Human Neutrophils Produce Antifungal Extracellular Vesicles against <named-content content-type="genus-species">Aspergillus fumigatus</named-content>
title_sort	human neutrophils produce antifungal extracellular vesicles against <named-content content-type="genus-species">aspergillus fumigatus</named-content>
publisher	American Society for Microbiology
publishDate	2020
url	https://doaj.org/article/0c73dfd61b2a43bf9cf5f653d3927aec
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Human Neutrophils Produce Antifungal Extracellular Vesicles against <named-content content-type="genus-species">Aspergillus fumigatus</named-content>

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