Effects of human immunoglobulins on Cryptococcus neoformans morphology and proteome

TL;DR

Human immunoglobulins, especially IgA, affect the growth and structure of Cryptococcus neoformans, suggesting a role in its pathogenesis.

Contribution

This study reveals that normal human IgA significantly alters Cryptococcus neoformans morphology and proteome, linking IgA levels to fungal pathogenesis.

Findings

IgA inhibits Cryptococcus neoformans growth and alters capsular fiber organization.

IgA reduces protein synthesis and disrupts glucuronoxylomannan synthesis pathways in Cn.

Lower IgA levels in HIV patients may contribute to cryptococcal meningitis pathogenesis.

Abstract

Cryptococcus neoformans (Cn) is the main cause of fungal meningitis in people living with HIV. Perturbations in normal immunoglobulin (Ig) levels are observed in these individuals, but their association with Cn pathogenesis is unclear. Here, we investigated the physical and biological effects of normal (not elicited by known cryptococcal infection) human immunoglobulins (Igs), IgM, IgG, and IgA on Cn (strain H99). Each isotype affected the growth, surface morphology, and proteome of Cn. However, IgA had the most prominent effect. It induced growth inhibition after 24 h of co-culture with Cn, altered the structural organization of capsular fibers, and significantly reduced protein synthesis and proteins associated with intracellular glucuronoxylomannan (GXM) synthesis, such as those mediating transport of sugar precursors to Golgi and the cyclic AMP pathway. Together with prior data showing an association between reduced plasma IgA and HIV-associated cryptococcal meningitis (CM), our findings suggest that the influence of human IgA on Cn pathogenesis warrants further investigation.

Cryptococcal meningitis (CM) causes approximately 1,200,000 deaths annually in people living with HIV and is also a threat to individuals with non-HIV-associated immune-compromising conditions, such as organ transplant recipients and other patients receiving immunosuppressants. Prior work has shown that normal human immunoglobulins (Igs) bind Cryptococcus neoformans (Cn) and that plasma levels of IgM, IgG, and IgA differ as a function of CM status. We investigated how human IgM, IgG, and IgA affect Cn growth, morphology, and protein synthesis. We found that IgA has major effects on these aspects of Cn biology and lends plausibility to the hypothesis that previously reported reductions in IgA levels in HIV-associated CM may influence Cn pathogenesis. Overall, our findings show that antibody immunity to Cn is more complex than previously thought.

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