Suppression of Toll-like receptor-mediated signaling by Cryptococcus neoformans

Abstract Cryptococcus neoformans is an intracellular fungal pathogen, host defense to which is mediated by cellular immunity and Th1 immune responses. This microorganism is eliminated by nitric oxide (NO) produced from activated macrophages. In the current study, we elucidate the influence of C. neoformans on NO synthesis by macrophages activated via Toll-like receptors (TLR). A mouse alveolar macrophage cell line, MH-S, was activated by TLR ligands such as peptidoglycan (PGN), lipopolysaccharide (LPS) and CpG-oligo DNA (ODN) in the presence of IFN-ƒ×. These treatments caused NO synthesis measured by Griess method and expression of iNOS mRNA detected by RT-PCR. C. neoformans encapsulated strains, YC-11 and B3501, and an acapsular strain, Cap67, strongly inhibited these activities. For this suppression, physical interaction between MH-S and C. neoformans was requied, and heat-killed organism was not effective. Lipid fractions derived from C. neoformans did not show such inhibitory activity. This fungal microorganism inhibited the activation of NFƒÛB in TLR-transfected HEK293 cells using a luciferase reporter assay. These results suggest that C. neoformans may suppress the NO-mediated killing by alveolar macrophages activated via a TLR pathway.