Differences in cryptococcus neoformans capsular polysaccharide structure influence assembly of alternative complement pathway C3 convertase on fungal surfaces

Washburn, Ronald G.; Bryant-Varela, B.J.; Julian, N.C.; Bennett, John E.

doi:10.1016/0161-5890(91)90160-l

Cited by 35 publications

(28 citation statements)

References 21 publications

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“…C. gattii does not appear to activate the alternative pathway as potently as C. neoformans (28,31). One study found that C. gattii binds fewer C3 molecules than C. neoformans (28). A later report indicated that while the maximum amount of bound C3 did not differ significantly between species, there was more rapid accumulation of C3 on C. neoformans before a steady state was achieved (31).…”

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Role of Complement in Protection againstCryptococcus gattiiInfection

Mershon¹,

Vasuthasawat²,

Lawson³

et al. 2009

Infect Immun

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Previous studies have shown that the alternative pathway of complement activation plays an important role in protection against infection with Cryptococcus neoformans. Cryptococcus gattii does not activate the alternative pathway as well as C. neoformans in vitro. The role of complement in C. gattii infection in vivo has not been reported. In this study, we used mice deficient in complement components to investigate the role of complement in protection against a C. gattii isolate from an ongoing outbreak in northwestern North America. While factor B-deficient mice showed an enhanced rate of death, complement component C3-deficient mice died even more rapidly, indicating that the alternative pathway was not the only complement pathway contributing to protection against disease. Both C3-and factor B-deficient mice had increased fungal burdens in comparison to wild-type mice. Histopathology revealed an overwhelming fungal burden in the lungs of these complementdeficient mice, which undoubtedly prevented efficient gas exchange, causing death. Following the fate of radiolabeled organisms showed that both factor B-and C3-deficient mice were less effective than wild-type mice in clearing organisms. However, opsonization of C. gattii with complement components was not sufficient to prolong life in mice deficient in complement. Killing of C. gattii by macrophages in vitro was decreased in the presence of serum from factor B-and C3-deficient versus wild-type mice. In conclusion, we have demonstrated that complement activation is crucial for survival in C. gattii infection. Additionally, we have shown that the alternative pathway of complement activation is not the only complement pathway contributing to protection.

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“…The capsule serves as a site for activation and deposition of C3 fragments, mainly iC3b, which promote phagocytosis of the yeast (12). C. gattii does not appear to activate the alternative pathway as potently as C. neoformans (28,31). One study found that C. gattii binds fewer C3 molecules than C. neoformans (28).…”

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Role of Complement in Protection againstCryptococcus gattiiInfection

Mershon¹,

Vasuthasawat²,

Lawson³

et al. 2009

Infect Immun

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“…For instance, O-acetyl has been recognized as the major epitope for recognition of GXM by various monoclonal and polyclonal Abs (22,27,31,32) and as important for clearance of GXM from serum (31). Xylose has been shown to play a role in complement deposition on cryptococci and accumulation of GXM in the spleen (31,33,34). Neither xylose nor O-acetyl appeared to play a role in the inhibition of phagocytosis by GXM in vitro (26,31).…”

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O-Acetylation of Cryptococcal Capsular Glucuronoxylomannan Is Essential for Interference with Neutrophil Migration

Ellerbroek

Lefeber

Veghel

et al. 2004

The Journal of Immunology

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The capsular polysaccharide glucuronoxylomannan (GXM) of Cryptococcus neoformans has been shown to interfere with neutrophil migration. Although several receptors have been implied to mediate this process, the structural perspectives are unknown. Here, we assess the contribution of 6-O-acetylation and xylose substitution of the (1→3)-α-d-mannan backbone of GXM, the variable structural features of GXM, to the interference with neutrophil migration. We compare chemically deacetylated GXM and acetyl- or xylose-deficient GXM from genetically modified strains with wild-type GXM in their ability to inhibit the different phases of neutrophil migration. Additionally, we verify the effects of de-O-acetylation on neutrophil migration in vivo. De-O-acetylation caused a dramatic reduction of the inhibitory capacity of GXM in the in vitro assays for neutrophil chemokinesis, rolling on E-selectin and firm adhesion to endothelium. Genetic removal of xylose only marginally reduced the ability of GXM to reduce firm adhesion. In vivo, chemical deacetylation of GXM significantly reduced its ability to interfere with neutrophil recruitment in a model of myocardial ischemia (65% reduction vs a nonsignificant reduction in tissue myeloperoxidase, respectively). Our findings indicate that 6-O-acetylated mannose of GXM is a crucial motive for the inhibition of neutrophil recruitment.

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“…C3b attachment to polysaccharides exhibiting low reactivity with the thioester site is inefficient, and this inefficiency affects each round of amplification. The end result is that activation of the APC (i.e., amplification) can be weak or strong depending on the specificity of metastable C3b for the particular carbohydrate structures on that particle (6,12,19,26,36).…”

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Molecular Mechanisms of Target Recognition in an Innate Immune System: Interactions Among Factor H, C3b, and Target in the Alternative Pathway of Human Complement

Pangburn

Koistinen

et al. 2000

The Journal of Immunology

109

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In the alternative pathway of complement (APC) factor H is the primary control factor involved in discrimination between potential pathogens. The APC deposits C3b on possible Ags, and the interaction with factor H determines whether the initial C3b activates the APC. Factor H is composed of a linear array of 20 homologous short consensus repeats (SCR) domains with many functional sites. Three of these sites are involved in binding C3b and regulating complement activation; others bind to sialic acid and/or heparin and are responsible for host recognition. Using site-directed mutations we have examined the contributions of each of these sites to target discrimination and to functional activities of factor H. Decay acceleration by SCR1–4 of C3/C5 convertases bound to nonactivators was strongly dependent on SCR domains 11–15 and 16–20. Loss of these regions caused a 97% loss of activity, with SCR16–20 being the most critical (>90% loss). On APC activators the pattern of site usage was different and unique on each. On yeast, deletion of the 10 C-terminal domains (SCR11–20) had no effect on specific activity. On rabbit erythrocytes, this deletion caused loss of 75% of the specific activity. An examination of binding affinity to C3b on the four cell types demonstrated that factor H exhibits a unique pattern of SCR involvement on each cell. The results reveal a complex molecular mechanism of discrimination between microbes and host in this ancient innate defense system and help explain the different rates and intensities of APC activation on different biological particles.

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Differences in cryptococcus neoformans capsular polysaccharide structure influence assembly of alternative complement pathway C3 convertase on fungal surfaces

Cited by 35 publications

References 21 publications

Role of Complement in Protection againstCryptococcus gattiiInfection

Role of Complement in Protection againstCryptococcus gattiiInfection

O-Acetylation of Cryptococcal Capsular Glucuronoxylomannan Is Essential for Interference with Neutrophil Migration

Molecular Mechanisms of Target Recognition in an Innate Immune System: Interactions Among Factor H, C3b, and Target in the Alternative Pathway of Human Complement

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