Opsonization of Cryptococcus neoformans by human anticryptococcal glucuronoxylomannan antibodies
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Published on: February 14, 2011
1Department of Medicine, Albert Einstein College of Medicine, Bronx, New York 10461, USA.
Abstract:
Cryptococcal meningitis occurs in 6 to 8% of human immunodeficiency virus-infected individuals. Despite the availability of powerful antifungal agents that are active against Cryptococcus neoformans, these drugs generally fail to cure cryptococcal infections in immunocompromised hosts. Alternative approaches to prevention and therapy of cryptococcosis are urgently needed. Complement promotes phagocytosis of C. neoformans, but human antibodies to cryptococcal capsular polysaccharide have not been shown to function as complement-independent opsonins. The goal of our studies was to characterize the in vitro biological function of human antibodies to glucuronoxylomannan (GXM) from individuals immunized with a GXM-tetanus toxoid (GXM-TT) vaccine. We studied sera from nine vaccinees that manifested good serologic responses to GXM-TT. The results indicate that GXM-TT-elicited antibodies promote phagocytosis of C. neoformans by both murine J774 cells and human peripheral blood mononuclear cells (PBMCs). The two sera with the highest titers of anti-GXM immunoglobulin G2 antibodies were the most opsonic. When PBMC Fc gamma RIIa receptors were blocked, a 75% decrease in phagocytosis occurred following incubation of the PBMCs with C. neoformans opsonized with these sera. Our data indicate that, in the absence of complement, human anti-GXM-TT antibodies are opsonic and that antibodies of the immunoglobulin G2 isotype are effective opsonins.
Insights
Human antibodies against cryptococcal glucuronoxylomannan (GXM) promote phagocytosis of C. neoformans in immunocompromised individuals. Immunoglobulin G2 antibodies are particularly effective opsonins, offering a potential new therapeutic strategy.
Area of Science:
- Immunology
- Infectious Diseases
- Vaccinology
Background:
- Cryptococcal meningitis affects 6-8% of HIV-infected individuals, often with poor outcomes despite antifungal treatments.
- Current therapies struggle to clear Cryptococcus neoformans in immunocompromised hosts, necessitating novel prevention and treatment strategies.
- While complement aids C. neoformans phagocytosis, human antibodies to its capsular polysaccharide have not demonstrated complement-independent opsonization.
Purpose of the Study:
- To investigate the in vitro function of human antibodies targeting glucuronoxylomannan (GXM), a key component of the C. neoformans capsule.
- To assess the opsonic capacity of antibodies generated following immunization with a GXM-tetanus toxoid (GXM-TT) vaccine.
Main Methods:
- Sera from nine GXM-TT vaccinees with robust serologic responses were analyzed.
- Phagocytosis assays were performed using murine J774 cells and human peripheral blood mononuclear cells (PBMCs).
- Fc gamma RIIa receptor blockade on PBMCs was employed to determine the role of specific antibody-dependent cellular mechanisms.
Main Results:
- Antibodies from GXM-TT vaccinees effectively promoted C. neoformans phagocytosis by both murine and human cells.
- Sera with higher titers of anti-GXM immunoglobulin G2 (IgG2) antibodies exhibited enhanced opsonic activity.
- Blocking Fc gamma RIIa receptors on PBMCs reduced phagocytosis by 75%, indicating the importance of this receptor-mediated process.
Conclusions:
- Human anti-GXM-TT antibodies function as effective opsonins in a complement-independent manner.
- Immunoglobulin G2 (IgG2) isotype antibodies are particularly potent in mediating phagocytosis of C. neoformans.
- These findings support the development of GXM-based vaccines and antibody-based therapies for cryptococcosis, especially in immunocompromised populations.
