Cargando…

Aspergillus-Derived Galactosaminogalactan Triggers Complement Activation on Human Platelets

Invasive fungal infections caused by Aspergillus (A.) and Mucorales species still represent life-threatening diseases in immunocompromised individuals, and deeper knowledge about fungal interactions with elements of innate immunity, such as complement and platelets, appears essential for optimized t...

Descripción completa

Detalles Bibliográficos
Autores principales: Deshmukh, Hemalata, Speth, Cornelia, Sheppard, Donald C., Neurauter, Magdalena, Würzner, Reinhard, Lass-Flörl, Cornelia, Rambach, Günter
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7573070/
https://www.ncbi.nlm.nih.gov/pubmed/33123129
http://dx.doi.org/10.3389/fimmu.2020.550827
_version_ 1783597371122253824
author Deshmukh, Hemalata
Speth, Cornelia
Sheppard, Donald C.
Neurauter, Magdalena
Würzner, Reinhard
Lass-Flörl, Cornelia
Rambach, Günter
author_facet Deshmukh, Hemalata
Speth, Cornelia
Sheppard, Donald C.
Neurauter, Magdalena
Würzner, Reinhard
Lass-Flörl, Cornelia
Rambach, Günter
author_sort Deshmukh, Hemalata
collection PubMed
description Invasive fungal infections caused by Aspergillus (A.) and Mucorales species still represent life-threatening diseases in immunocompromised individuals, and deeper knowledge about fungal interactions with elements of innate immunity, such as complement and platelets, appears essential for optimized therapy. Previous studies showed that galactosaminogalactan secreted by A. fumigatus and A. flavus is deposited on platelets, thereby inducing their activation. Since the altered platelet surface is a putative trigger for complement activation, we aimed to study the interplay of platelets with complement in the presence of fungal GAG. Culture supernatants (SN) of A. fumigatus and A. flavus both induced not only GAG deposition but also subsequent deposition of complement C3 fragments on the platelet surface. The SN of a Δuge3 mutant of A. fumigatus, which is unable to synthesize GAG, did not induce complement deposition on platelets, nor did the SN of other Aspergillus species and all tested Mucorales. Detailed analysis revealed that GAG deposition itself triggered the complement cascade rather than the GAG-induced phosphatidylserine exposure. The lectin pathway of complement could be shown to be crucially involved in this process. GAG-induced complement activation on the platelet surface was revealed to trigger processes that might contribute to the pathogenesis of invasive aspergillosis by A. fumigatus or A. flavus. Both pro-inflammatory anaphylatoxins C3a and C5a arose when platelets were incubated with SN of these fungal species; these processes might favor excessive inflammation after fungal infection. Furthermore, platelets were stimulated to shed microparticles, which are also known to harbor pro-inflammatory and pro-coagulant properties. Not only did early processes of the complement cascade proceed on platelets, but also the formation of the terminal complement C5b-9 complex was detected on platelets after incubation with fungal SN. Subsequently, reduced viability of the platelets could be shown, which might contribute to the lowered platelet numbers found in infected patients. In summary, fungal GAG initiates an interplay between complement and platelets that can be supposed to contribute to excessive inflammation, thrombocytopenia, and thrombosis, which are important hallmarks of fatal invasive mycoses.
format Online
Article
Text
id pubmed-7573070
institution National Center for Biotechnology Information
language English
publishDate 2020
publisher Frontiers Media S.A.
record_format MEDLINE/PubMed
spelling pubmed-75730702020-10-28 Aspergillus-Derived Galactosaminogalactan Triggers Complement Activation on Human Platelets Deshmukh, Hemalata Speth, Cornelia Sheppard, Donald C. Neurauter, Magdalena Würzner, Reinhard Lass-Flörl, Cornelia Rambach, Günter Front Immunol Immunology Invasive fungal infections caused by Aspergillus (A.) and Mucorales species still represent life-threatening diseases in immunocompromised individuals, and deeper knowledge about fungal interactions with elements of innate immunity, such as complement and platelets, appears essential for optimized therapy. Previous studies showed that galactosaminogalactan secreted by A. fumigatus and A. flavus is deposited on platelets, thereby inducing their activation. Since the altered platelet surface is a putative trigger for complement activation, we aimed to study the interplay of platelets with complement in the presence of fungal GAG. Culture supernatants (SN) of A. fumigatus and A. flavus both induced not only GAG deposition but also subsequent deposition of complement C3 fragments on the platelet surface. The SN of a Δuge3 mutant of A. fumigatus, which is unable to synthesize GAG, did not induce complement deposition on platelets, nor did the SN of other Aspergillus species and all tested Mucorales. Detailed analysis revealed that GAG deposition itself triggered the complement cascade rather than the GAG-induced phosphatidylserine exposure. The lectin pathway of complement could be shown to be crucially involved in this process. GAG-induced complement activation on the platelet surface was revealed to trigger processes that might contribute to the pathogenesis of invasive aspergillosis by A. fumigatus or A. flavus. Both pro-inflammatory anaphylatoxins C3a and C5a arose when platelets were incubated with SN of these fungal species; these processes might favor excessive inflammation after fungal infection. Furthermore, platelets were stimulated to shed microparticles, which are also known to harbor pro-inflammatory and pro-coagulant properties. Not only did early processes of the complement cascade proceed on platelets, but also the formation of the terminal complement C5b-9 complex was detected on platelets after incubation with fungal SN. Subsequently, reduced viability of the platelets could be shown, which might contribute to the lowered platelet numbers found in infected patients. In summary, fungal GAG initiates an interplay between complement and platelets that can be supposed to contribute to excessive inflammation, thrombocytopenia, and thrombosis, which are important hallmarks of fatal invasive mycoses. Frontiers Media S.A. 2020-10-06 /pmc/articles/PMC7573070/ /pubmed/33123129 http://dx.doi.org/10.3389/fimmu.2020.550827 Text en Copyright © 2020 Deshmukh, Speth, Sheppard, Neurauter, Würzner, Lass-Flörl and Rambach. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Immunology
Deshmukh, Hemalata
Speth, Cornelia
Sheppard, Donald C.
Neurauter, Magdalena
Würzner, Reinhard
Lass-Flörl, Cornelia
Rambach, Günter
Aspergillus-Derived Galactosaminogalactan Triggers Complement Activation on Human Platelets
title Aspergillus-Derived Galactosaminogalactan Triggers Complement Activation on Human Platelets
title_full Aspergillus-Derived Galactosaminogalactan Triggers Complement Activation on Human Platelets
title_fullStr Aspergillus-Derived Galactosaminogalactan Triggers Complement Activation on Human Platelets
title_full_unstemmed Aspergillus-Derived Galactosaminogalactan Triggers Complement Activation on Human Platelets
title_short Aspergillus-Derived Galactosaminogalactan Triggers Complement Activation on Human Platelets
title_sort aspergillus-derived galactosaminogalactan triggers complement activation on human platelets
topic Immunology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7573070/
https://www.ncbi.nlm.nih.gov/pubmed/33123129
http://dx.doi.org/10.3389/fimmu.2020.550827
work_keys_str_mv AT deshmukhhemalata aspergillusderivedgalactosaminogalactantriggerscomplementactivationonhumanplatelets
AT spethcornelia aspergillusderivedgalactosaminogalactantriggerscomplementactivationonhumanplatelets
AT shepparddonaldc aspergillusderivedgalactosaminogalactantriggerscomplementactivationonhumanplatelets
AT neurautermagdalena aspergillusderivedgalactosaminogalactantriggerscomplementactivationonhumanplatelets
AT wurznerreinhard aspergillusderivedgalactosaminogalactantriggerscomplementactivationonhumanplatelets
AT lassflorlcornelia aspergillusderivedgalactosaminogalactantriggerscomplementactivationonhumanplatelets
AT rambachgunter aspergillusderivedgalactosaminogalactantriggerscomplementactivationonhumanplatelets