Tumor necrosis factor-inducing activities of Cryptococcus neoformans components

Abstract

Cryptococcus neoformans-induced tumor necrosis factor alpha (TNF-␣) 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 ␤(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-␣ 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-␣ 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 g of MP per ml was sufficient to produce moderate but significant elevations of TNF-␣ release. Maximal MP-induced TNF-␣ 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-␣ production, although the participation of other cell types could not be excluded. The presence of complement-sufficient plasma was a necessary requirement for TNF-␣ induction by GXM, GalXM, and low doses of MP. High MP concentrations (100 g/ml) were also capable of stimulating TNF-␣ production in the absence of plasma. These data indicate that soluble products released by C. neoformans are capable of inducing TNF-␣ 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. Cryptococcus neoformans is a predominantly saprophytic yeast that can cause serious infections, mostly in individuals with compromised cellular immunity. Cryptococcosis is the fourth most common cause of mortality in patients with AIDS (7, 16). Currently, 4% of patients with AIDS in the United Kingdom (18), 5 to 10% of AIDS patients in the United States (10, 13), and an increasing percentage in the developing countries are known to have developed cryptococcosis (34, 42). The yeast, occurring as four serotypes, is surrounded by a capsule primarily composed of glucuronoxylomannan (GXM) (9) and composed, to a lesser extent, of galactoxylomannan (GalXM) and mannoproteins (MP). Approximately 80% of the clinical isolates in the United States are of serotype A (21). Infection follows inhalation from environmental sources of poorly encapsulated yeasts, which are normally ingested and killed by pulmonary host defenses (4, 40). Increased capsule production and replication within the lung may lead to dissemination to other tissues, frequently resulting in fatal meningoencephalitis. It is likely that the capsule acts as a virulence factor by inhibiting opsonophagocytosis (19, 20, 30), although the specific mechanisms for this effect are no...

Cryptococcus neoformans capsular polysaccharide component galactoxylomannan induces apoptosis of human T-cells through activation of caspase-8

“…GalXM has generally been considered a minor component of C. neoformans capsular material and there are only a few reports on its immunoregulatory activity. GalXM was reported to induce TNF-α production by PBMC (Delfino et al, 1996;Chaka et al, 1997) and to bind to human neutrophils via CD18 (Dong and Murphy, 1997). Biochemical studies reveal that GalXM and GXM are structurally different (Vaishnav et al, 1998).…”

Cryptococcal capsular glucuronoxylomannan reduces ischaemia‐related neutrophil influx

“…In those studies the effects of GXM evolved in the absence of serum and were therefore independent of complement activation. However, as several data indicate that GXM presumably activates the complement system [12,[54][55][56], the resulting generation of the chemoattracting factor C5a in the bloodstream might be an additional mechanism underlying the observed interference with leucocyte migration. The presence of massive amounts of C5a in the bloodstream would theoretically prevent neutrophils from responding properly to other chemoattracting substances present in the inflamed tissues.…”

“…Error bars represent the standard deviation of the calculated mean of treatment groups. that GXM stimulates complement has been mainly deduced from studies demonstrating that (1) complement activation by whole encapsulated cryptococci is related to the amount of xylose residues in GXM [59,61], and that (2) GXMinduced cytokine production depends on a heat-labile factor in serum that can be abrogated by antibodies against complement factor C3 [54][55][56].…”

Complement and fungal pathogens: an update

“…125 The presence of complement is a prerequisite for TNF-a induction. 125,126 Opsonised C. neoformans also provokes the release of TNF-a from DC. 107 The produced TNF-a efficiently supports ingestion of the encapsulated yeast by CR3-bearing macrophages.…”