Tumor necrosis factor-inducing activities of Cryptococcus neoformans components

Abstract

Cryptococcus neoformans-induced tumor necrosis factor alpha (TNF-α) production may lead to increased human immunodeficiency virus replication in patients with AIDS. In order to identify cryptococcal components that are predominantly responsible for stimulating TNF production, various concentrations of glucuronoxylomannan (GXM), galactoxylomannan (GalXM), mannoproteins (MP), and β(1-3) glucan were added to whole-blood cultures. All of the cryptococcal components tested, as well as whole heat-killed cryptococci, were capable of inducing TNF-α release in a dose-dependent manner. MP were significantly more potent than any of the other cryptococcal components tested or heat-killed cryptococci in stimulating TNF-α production (P < 0.05). GXM, in contrast, was significantly less potent in this activity than either GalXM or MP (P < 0.05). As little as 0.5 μg of MP per ml was sufficient to produce moderate but significant elevations of TNF-α release. Maximal MP-induced TNF-α levels were similar to those induced by Salmonella enteritidis lipopolysaccharide, our positive control. Further experiments using isolated leukocytes suggested that monocytes were the cell population mainly responsible for TNF-α production, although the participation of other cell types could not be excluded. The presence of complement-sufficient plasma was a necessary requirement for TNF-α induction by GXM, GalXM, and low doses of MP. High MP concentrations (100 μg/ml) were also capable of stimulating TNF-α production in the absence of plasma. These data indicate that soluble products released by C. neoformans are capable of inducing TNF- α secretion in human leukocytes. This may be clinically relevant, since high concentrations of such products are frequently found in the body fluids of AIDS patients infected with C. neoformans.