Antibody to
            <i>Cryptococcus neoformans</i>
            Glucuronoxylomannan Inhibits the Release of Capsular Antigen

Martinez, Luis R.; Moussai, Dariush; Casadevall, Arturo

doi:10.1128/iai.72.6.3674-3679.2004

Cited by 52 publications

(42 citation statements)

References 22 publications

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“…A higher 18B7 concentration of 50 g/ml paradoxically decreased levels of GXM release, likely due to the cross-linking and aggregation of fungal cells, which was visualized by india ink stain, effectively locking the capsule in place. This phenomenon has been described previously with live C. neoformans and concentrations of 18B7 50 g/ml and higher (49). At these higher antibody concentrations, the reduction in GXM released due to cross-linking overwhelms the amount of GXM hydrolyzed by 18B7.…”

Section: Discussionmentioning

confidence: 58%

A Monoclonal Antibody to Cryptococcus neoformans Glucuronoxylomannan Manifests Hydrolytic Activity for Both Peptides and Polysaccharides

Bowen

Wear

Cordero

et al. 2017

Journal of Biological Chemistry

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Edited by Luke O'NeillStudies in the 1980s first showed that some natural antibodies were "catalytic" and able to hydrolyze peptide or phosphodiester bonds in antigens. Many naturally occurring catalytic antibodies have since been isolated from human sera and associated with positive and negative outcomes in autoimmune disease and infection. The function and prevalence of these antibodies, however, remain unclear. A previous study suggested that the 18B7 monoclonal antibody against glucuronoxylomannan (GXM), the major component of the Cryptococcus neoformans polysaccharide capsule, hydrolyzed a peptide antigen mimetic. Using mass spectrometry and Förster resonance energy transfer techniques, we confirm and characterize the hydrolytic activity of 18B7 against peptide mimetics and show that 18B7 is able to hydrolyze an oligosaccharide substrate, providing the first example of a naturally occurring catalytic antibody for polysaccharides. Additionally, we show that the catalytic 18B7 antibody increases release of capsular polysaccharide from fungal cells. A serine protease inhibitor blocked peptide and oligosaccharide hydrolysis by 18B7, and a putative serine protease-like active site was identified in the light chain variable region of the antibody. An algorithm was developed to detect similar sites present in unique antibody structures in the Protein Data Bank. The putative site was found in 14 of 63 (22.2%) catalytic antibody structures and 119 of 1602 (7.4%) antibodies with no annotation of catalytic activity. The ability of many antibodies to cleave antigen, albeit slowly, supports the notion that this activity is an important immunoglobulin function in host defense. The discovery of GXM hydrolytic activity suggests new therapeutic possibilities for polysaccharide-binding antibodies.A central tenet in immunology is that immunoglobulin (Ig) variable (V) 2 regions bind antigen (Ag) and that the molecule's constant regions activate complement components or cellular receptors, triggering downstream immune pathways such as phagocytosis, granule release, cell-mediated cytotoxicity, and complement-mediated cytotoxicity. Research has also shown that antibodies possess important direct effects on Ag, such as neutralization of toxins or virions, bacterial agglutination, and precipitation of soluble Ag. Although it has long been accepted that each of these Ig functions are mediated by the binding of an antibody paratope to an Ag epitope, research in 1975 first showed that antibodies could be generated that not only bound Ag but also catalyzed a chemical reaction in the Ag substrate (1). Over the next 2 decades, many catalytic antibodies were generated against haptenic transition state analogues to catalyze a wide array of chemical reactions, a strategy first proposed by enzymologist W. Jencks in 1969 (2). This strategy has since been used to generate antibody catalysts for many distinct chemical reactions, albeit with reaction rates usually much slower than natural enzymes. The first indication that some naturally occurri...

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Section: Discussionmentioning

confidence: 58%

A Monoclonal Antibody to Cryptococcus neoformans Glucuronoxylomannan Manifests Hydrolytic Activity for Both Peptides and Polysaccharides

Bowen

Wear

Cordero

et al. 2017

Journal of Biological Chemistry

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“…The results were consistent with the upregulation of the entire fatty acid synthesis pathway seen in the microarray when H99 was bound by mAb 18B7. Given prior observations that mAb 18B7 inhibits polysaccharide shedding in vitro (8) and biofilm formation (9), together with recent evidence that the major component of the capsule, GXM (27), and other major virulence factors (28), are exported to the cell exterior in lipid vesicles, our data suggest an association between lipid metabolism and capsule production/shedding, which appears to be reflected in the metabolic changes observed. Additionally, it is possible that changes in lipid metabolism are seen because mAb 18B7 binds very close to the cell wall, and this binding may somehow perturb membrane lipids that in turn produce regulatory changes in lipid metabolism (29).…”

Section: Figurementioning

confidence: 91%

“…For the human pathogenic fungus C. neoformans, Ab-mediated protection is associated with interference of polysaccharide release and biofilm formation (8,9). For example, the IgG1 mAb 18B7 and IgM mAb 12A1 each inhibit biofilm formation and polysaccharide release, while the IgM mAb 13F1 has no effect on either phenomenon (9).…”

Section: Discussionmentioning

confidence: 99%

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Ab binding alters gene expression in Cryptococcus neoformans and directly modulates fungal metabolism

McClelland¹,

Nicola²,

Prados-Rosales³

et al. 2010

J. Clin. Invest.

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“…Antibodies to the polysaccharide capsule can enhance survival (10), promote phagocytosis (29), affect complement activation (19), alter cytokine expression in vivo (11), clear serum polysaccharide antigen (14), enhance antigen presentation (38), and modulate expression of immunologically important molecules (26). In addition, we recently demonstrated that specific antibody could inhibit GXM release from cells, possibly by cross-linking GXM molecules in the capsule (22). Since C. neoformans can form biofilms on medical devices that presumably contain polysaccharide components (41), this finding raised the intriguing possibility that antibody to GXM would also interfere with cryptococcal biofilm formation.…”

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confidence: 99%

Specific Antibody Can Prevent Fungal Biofilm Formation and This Effect Correlates with Protective Efficacy

2005

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One of the most troublesome medical problems today is infection of prosthetic devices with organisms that form polysaccharide biofilms. This combined with increasing antimicrobial drug resistance is making many infectious diseases incurable. Cryptococcus neoformans is a human-pathogenic fungus that has a polysaccharide capsule and can form biofilms in prosthetic medical devices. We developed a system to study cryptococcal biofilm formation in vitro and studied the effect of antibody to the C. neoformans capsular polysaccharide on this process. C. neoformans biofilm formation was dependent on the presence of a polysaccharide capsule and correlated with the ability of capsular polysaccharide to bind the polystyrene solid support. Protective antibodies prevented biofilm formation whereas nonprotective antibodies were not effective. The mechanism of antibody action involved interference with capsular polysaccharide release from the fungal cell. In contrast, lactoferrin, an effector molecule of innate immune mechanisms, was unable to prevent fungal biofilm formation despite its efficacy against bacterial biofilms. Our results suggest a new role of adaptive humoral immunity whereby some antibodies can inhibit biofilm formation by encapsulated organisms. Vaccines that elicit antibody responses to capsular antigens and/or passive transfer of antibodies to microbial polysaccharides may be useful in preventing biofilm formation.

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Antibody to Cryptococcus neoformans Glucuronoxylomannan Inhibits the Release of Capsular Antigen

Cited by 52 publications

References 22 publications

A Monoclonal Antibody to Cryptococcus neoformans Glucuronoxylomannan Manifests Hydrolytic Activity for Both Peptides and Polysaccharides

A Monoclonal Antibody to Cryptococcus neoformans Glucuronoxylomannan Manifests Hydrolytic Activity for Both Peptides and Polysaccharides

Ab binding alters gene expression in Cryptococcus neoformans and directly modulates fungal metabolism

Specific Antibody Can Prevent Fungal Biofilm Formation and This Effect Correlates with Protective Efficacy

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