Modulation of host cell inflammatory responses by Cryptococcus neoformans

Abstract

The ubiquitous pathogen Cryptococcus neoformans is the most common cause of fungal meningoencephalitis worldwide. This fungus produces an antiphagocytic polysaccharide capsule, which is linked to virulence in vivo. Passive transfer of anticapsular antibodies enhances host survival in experimental murine infection, however, the mechanisms for antibody protection are not fully understood. Anticapsular antibodies are more efficacious in the presence of the cytokine interferon-gamma or the antifungal drug amphotericin B, suggesting a role for these agents in host cell immunomodulation.;The synthesis of nitric oxide (NO) by inducible nitric oxide synthase in host effector cells is an important factor in anticryptococcal immunity. We and others observed that incubation of C. neoformans cells with interferon-gamma-stimulated murine macrophages did not induce NO, and in fact, inhibited cytokine-induced NO. Inhibition was dependent on cell-cell contact, but not on the fungal strain or presence of a cryptococcal capsule. Inclusion of anticapsular antibodies reversed the inhibition of NO synthesis by encapsulated, but not acapsular C. neoformans. Furthermore, purified capsular polysaccharides in the presence of specific antipolysaccharide IgG enhanced cytokine-induced NO, implicating macrophage FcgammaR crosslinking as a mechanism of protection by anticryptococcal antibodies. Amphotericin B also enhanced cytokine-induced macrophage NO production alone and in combination with antibody-polysaccharide immune complexes, suggesting an additional mechanism of amphotericin B efficacy.;Infection with C. neoformans often results in a weak inflammatory response. Lack of leukocyte infiltration during cryptococcosis has been attributed to the immunodeficient status of the host, but is also observed in immunocompetent individuals and experimental animals. Leukocyte activation and recruitment are regulated by the production of chemotactic cytokines (chemokines) by cells of the vasculature and target organs. C. neoformans failed to induce chemokines in primary human endothelial cells and primary human astrocytes, and differentially inhibited cytokine-induced chemokine expression. C. neoformans also inhibited cytokine-induced NO in astrocytes. As with macrophages, these effects were independent of cryptococcal capsule and strain, and were not specific to a particular cytokine, but reflected a block in proinflammatory signaling.;Therefore, C. neoformans may regulate the host immune response at the level of effector cells, reducing the activation and recruitment of anticryptococcal leukocytes and diminishing host resistance.