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

• Published in: The Journal of clinical investigation Vol. 120; no. 4; pp. 1355 - 1361
• Main Authors: McClelland, Erin E, Nicola, André M, Prados-Rosales, Rafael, Casadevall, Arturo
• Format: Journal Article
• Language: English
• Published: United States American Society for Clinical Investigation 01-04-2010
• Subjects: Amphotericin B - pharmacology; Antibodies, Fungal - immunology; Antibodies, Monoclonal - immunology; Antimicrobial agents; Bacterial Capsules - immunology; Biofilms; Biomedical research; Cryptococcus; Cryptococcus neoformans; Cryptococcus neoformans - drug effects; Cryptococcus neoformans - genetics; Cryptococcus neoformans - immunology; Cryptococcus neoformans - metabolism; Fatty acids; Gene expression; Gene Expression Regulation, Fungal; Genetic aspects; Immunoglobulins; Lipid Metabolism; Metabolism; Microbial metabolism; Physiological aspects; Protein binding; Proteins; Streptococcus infections; United States
• ISSN: 0021-9738; 1558-8238
• DOI: 10.1172/JCI38322

Abs facilitate humoral immunity via the classical mechanisms of opsonization, complement activation, Ab-dependent cellular cytotoxicity, and toxin/viral neutralization. There is also evidence that some Abs mediate direct antimicrobial effects. For example, Ab binding to the polysaccharide capsule of the human pathogenic fungus Cryptococcus neoformans promotes opsonization but also inhibits polysaccharide release and biofilm formation. To investigate whether Ab binding affects C. neoformans directly, we analyzed fungal gene expression after binding of protective and nonprotective mAbs. The 2 IgM Abs and 1 IgG1 Ab tested each induced different changes in gene expression. The protective IgG1 mAb upregulated genes encoding proteins involved in fatty acid synthesis, the protective IgM mAb downregulated genes encoding proteins required for protein translation, and the nonprotective IgM mAb had modest effects on gene expression. Differences in gene expression correlated with mAb binding to different locations of the capsule. Of the 3 Abs tested, the protective IgG1 mAb bound to C. neoformans closest to the cell wall, produced specific differences in the pattern of phosphorylated proteins, caused changes in lipid metabolism, and resulted in increased susceptibility to the antifungal drug amphotericin B. These results suggest what we believe to be a new mode of action for Ab-mediated immunity and raise the possibility that immunoglobulins mediate cross talk between microbes and hosts through their effects on microbial metabolism.