Chemokine production by cytokine-treated human endothelial cells and astrocytes is altered by Cryptococcus neoformans and restored by interferon-γ

Cryptococcus neoformans is a fungal pathogen which afflicts 10% of AIDS patients worldwide. This organism is acquired by inhalation and often leads to meningitis in the immunocompromised host. The inflammatory response to this infection is poor. Little is known regarding interaction of this fungus with cells of the blood-brain-barrier, which regulate leukocyte migration into the central nervous system. We studied the effect of C. neoformans on chemokine production by primary human endothelial cells and astrocytes treated with various cytokines with and without interferon-γ. We measured monocyte chemotactic protein-1, interleukin-8, and interferon-inducible protein-10 (IP-10) at the message and protein levels by ribonuclease protection assay and ELISA respectively. We found that C. neoformans altered chemokine production in a cytokine-dependent fashion, depending upon the cell type studied. In astrocytes, downregulation of IP-10 paralleled decreases in cytokine-induced nitric oxide, suggesting one potential mechanism for chemokine regulation. In certain cases, interferon-γ could reverse the inhibitory effect of C. neoformans on chemokine production, suggesting a block in physical interaction between the human cells and C. neoformans. In support of this, we found that both endothelial cells and astrocytes were capable of internalizing C. neoformans, and we are investigating interferon-γ modulation of phagocytosis. We hypothesize that C. neoformans may selectively alter chemokine expression by endothelial cells and astrocytes in vivo, effectively reducing leukocyte emigration into areas of fungal invasion in the brain.