Linkage Specificity and Role of Properdin in Activation of the Alternative Complement Pathway by Fungal Glycans

ABSTRACT Fungal cell walls are predominantly composed of glucans, mannans, and chitin. Recognition of these glycans by the innate immune system is a critical component of host defenses against the mycoses. Complement, an important arm of innate immunity, plays a significant role in fungal pathogenes...

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Autores principales:	Sarika Agarwal, Charles A. Specht, Haibin Huang, Gary R. Ostroff, Sanjay Ram, Peter A. Rice, Stuart M. Levitz
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Lenguaje:	EN
Publicado:	American Society for Microbiology 2011
Materias:	Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/1efda269015e4fbaa2af862b7964b80d
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spelling	oai:doaj.org-article:1efda269015e4fbaa2af862b7964b80d2021-11-15T15:38:57ZLinkage Specificity and Role of Properdin in Activation of the Alternative Complement Pathway by Fungal Glycans10.1128/mBio.00178-112150-7511https://doaj.org/article/1efda269015e4fbaa2af862b7964b80d2011-11-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.00178-11https://doaj.org/toc/2150-7511ABSTRACT Fungal cell walls are predominantly composed of glucans, mannans, and chitin. Recognition of these glycans by the innate immune system is a critical component of host defenses against the mycoses. Complement, an important arm of innate immunity, plays a significant role in fungal pathogenesis, especially the alternative pathway (AP). Here we determine that the glycan monosaccharide composition and glycosidic linkages affect AP activation and C3 deposition. Furthermore, properdin, a positive regulator of the AP, contributes to these functions. AP activation by glycan particles that varied in composition and linkage was measured by C3a generation in serum treated with 10 mM EGTA and 10 mM Mg2+ (Mg-EGTA-treated serum) (AP specific; properdin functional) or Mg-EGTA-treated serum that lacked functional properdin. Particles that contained either β1→3 or β1→6 glucans or both generated large and similar amounts of C3a when the AP was intact. Blocking properdin function resulted in 5- to 10-fold-less C3a production by particulate β1→3 glucans. However, particulate β1→6 glucans generated C3a via the AP only in the presence of intact properdin. Interestingly, zymosan and glucan-mannan particles (GMP), which contain both β-glucans and mannans, also required properdin to generate C3a. The β1→4 glycans chitin and chitosan minimally activated C3 even when properdin was functional. Finally, properdin binding to glucan particles (GP) and zymosan in serum required active C3. Properdin colocalized with bound C3, suggesting that in the presence of serum, properdin bound indirectly to glycans through C3 convertases. These findings provide a better understanding of how properdin facilitates AP activation by fungi through interaction with the cell wall components. IMPORTANCE Invasive fungal infections have increased in incidence with the widespread use of immunosuppressive therapy and invasive procedures. Activation of the complement system contributes to innate immunity against fungi by generating chemoattractants that recruit white blood cells and by coating the pathogen with complement fragments that “mark” them for phagocytosis. The fungal cell wall activates complement in an antibody-independent manner through the alternative pathway (AP). Properdin is a positive regulator of the AP. This study elucidates how the specificity of cell wall glycan linkages affects AP activation and the role properdin plays in this process. Particulate β1→3 glucans activated the AP even in the absence of properdin, while β1→6 glucans required properdin for AP activation. In contrast, the β1→4 glycans chitin and chitosan failed to activate the AP. These findings enhance our mechanistic understanding of how fungi activate complement and have implications for the use of glycans in biomedical applications.Sarika AgarwalCharles A. SpechtHaibin HuangGary R. OstroffSanjay RamPeter A. RiceStuart M. LevitzAmerican Society for MicrobiologyarticleMicrobiologyQR1-502ENmBio, Vol 2, Iss 5 (2011)
institution	DOAJ
collection	DOAJ
language	EN
topic	Microbiology QR1-502
spellingShingle	Microbiology QR1-502 Sarika Agarwal Charles A. Specht Haibin Huang Gary R. Ostroff Sanjay Ram Peter A. Rice Stuart M. Levitz Linkage Specificity and Role of Properdin in Activation of the Alternative Complement Pathway by Fungal Glycans
description	ABSTRACT Fungal cell walls are predominantly composed of glucans, mannans, and chitin. Recognition of these glycans by the innate immune system is a critical component of host defenses against the mycoses. Complement, an important arm of innate immunity, plays a significant role in fungal pathogenesis, especially the alternative pathway (AP). Here we determine that the glycan monosaccharide composition and glycosidic linkages affect AP activation and C3 deposition. Furthermore, properdin, a positive regulator of the AP, contributes to these functions. AP activation by glycan particles that varied in composition and linkage was measured by C3a generation in serum treated with 10 mM EGTA and 10 mM Mg2+ (Mg-EGTA-treated serum) (AP specific; properdin functional) or Mg-EGTA-treated serum that lacked functional properdin. Particles that contained either β1→3 or β1→6 glucans or both generated large and similar amounts of C3a when the AP was intact. Blocking properdin function resulted in 5- to 10-fold-less C3a production by particulate β1→3 glucans. However, particulate β1→6 glucans generated C3a via the AP only in the presence of intact properdin. Interestingly, zymosan and glucan-mannan particles (GMP), which contain both β-glucans and mannans, also required properdin to generate C3a. The β1→4 glycans chitin and chitosan minimally activated C3 even when properdin was functional. Finally, properdin binding to glucan particles (GP) and zymosan in serum required active C3. Properdin colocalized with bound C3, suggesting that in the presence of serum, properdin bound indirectly to glycans through C3 convertases. These findings provide a better understanding of how properdin facilitates AP activation by fungi through interaction with the cell wall components. IMPORTANCE Invasive fungal infections have increased in incidence with the widespread use of immunosuppressive therapy and invasive procedures. Activation of the complement system contributes to innate immunity against fungi by generating chemoattractants that recruit white blood cells and by coating the pathogen with complement fragments that “mark” them for phagocytosis. The fungal cell wall activates complement in an antibody-independent manner through the alternative pathway (AP). Properdin is a positive regulator of the AP. This study elucidates how the specificity of cell wall glycan linkages affects AP activation and the role properdin plays in this process. Particulate β1→3 glucans activated the AP even in the absence of properdin, while β1→6 glucans required properdin for AP activation. In contrast, the β1→4 glycans chitin and chitosan failed to activate the AP. These findings enhance our mechanistic understanding of how fungi activate complement and have implications for the use of glycans in biomedical applications.
format	article
author	Sarika Agarwal Charles A. Specht Haibin Huang Gary R. Ostroff Sanjay Ram Peter A. Rice Stuart M. Levitz
author_facet	Sarika Agarwal Charles A. Specht Haibin Huang Gary R. Ostroff Sanjay Ram Peter A. Rice Stuart M. Levitz
author_sort	Sarika Agarwal
title	Linkage Specificity and Role of Properdin in Activation of the Alternative Complement Pathway by Fungal Glycans
title_short	Linkage Specificity and Role of Properdin in Activation of the Alternative Complement Pathway by Fungal Glycans
title_full	Linkage Specificity and Role of Properdin in Activation of the Alternative Complement Pathway by Fungal Glycans
title_fullStr	Linkage Specificity and Role of Properdin in Activation of the Alternative Complement Pathway by Fungal Glycans
title_full_unstemmed	Linkage Specificity and Role of Properdin in Activation of the Alternative Complement Pathway by Fungal Glycans
title_sort	linkage specificity and role of properdin in activation of the alternative complement pathway by fungal glycans
publisher	American Society for Microbiology
publishDate	2011
url	https://doaj.org/article/1efda269015e4fbaa2af862b7964b80d
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Linkage Specificity and Role of Properdin in Activation of the Alternative Complement Pathway by Fungal Glycans

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