Cryptococcal virulence: beyond the usual suspects

Abstract

In this issue of the JCI, the observation of the altered pathogenicity of a Cryptococcus neoformans glucosylceramide (GlcCer) mutant shines new light on the initiation of cryptococcal infection. Rittershaus and colleagues demonstrate that the cell surface glycosphingolipid GlcCer is essential for the fungus to grow in the extracellular environments of the host bloodstream and alveolar spaces of the lung, which, in contrast to the acidic intracellular environment of macrophages, are characterized by a neutral pH (see the related article beginning on page 1651). Their findings establish an unexpected connection between this glycosphingolipid and the fungal responses to physiological CO2 and pH. They also focus new attention on the therapeutic potential of anti-GlcCer antibodies found in convalescent sera.

Figure 1. Natural C. neoformans infection is initiated after inhalation of airborne spores or cells.

After reaching the lung alveoli, the organism is taken up by macrophages into their acidic lysosomes, where the organism divides and disseminates. The report from Rittershaus and colleagues in this issue of the JCI (2) shows that there is a critical extracellular growth phase after the organism reaches the lung, but before uptake by macrophages. In this phase, the organism encounters the neutral pH and physiological (~5%) CO₂ level that characterizes host tissues. Rittershaus et al. find that the fungal surface sphingolipid GlcCer is critical for growth under these specific conditions. Thus GlcCer is required for experimental murine infections that are initiated by inhalation (A), but not for infections initiated by injection (B).