Human IgM Inhibits the Formation of Titan-Like Cells in Cryptococcus neoformans.

Abstract

Human studies have shown associations between cryptococcal meningitis and reduced IgM memory B cell levels, and studies in IgM- and/or B cell-deficient mice have demonstrated increased dissemination from lungs to brain. Since immunoglobulins are part of the immune milieu that confronts in a human host, and its ability to form titan cells is an important virulence mechanism, we determined the effect of human immunoglobulins on titan cell formation (i) Fluorescence microscopy showed normal human IgG and IgM bind (ii) grown in titan cell-inducing medium with IgM, not IgG, inhibited titan-like cell formation. (iii) Absorption of IgM with laminarin or curdlan (branched and linear 1-3-beta-d-glucans, respectively) decreased this effect. (iv) Transmission electron microscopy revealed that cells grown with IgM had small capsules and unique features not seen with cells grown with IgG. (v) Comparative transcriptional analysis of cell wall, capsule, and stress response genes showed that grown with IgM, not IgG or phosphate-buffered saline (PBS), had decreased expression of chitin synthetase, , , and , and genes encoding cell wall carbohydrate synthetases α-1-3-glucan () and β-1,3-glucan (). IgM also decreased expression of and , genes encoding central regulators of stress response pathways and cell morphogenesis. Our data show human IgM affects morphology and suggest that the hypothesis that human immunoglobulins may affect virulence warrants further investigation.