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...

Previous studies have shown that tumor necrosis factor alpha (TNF-a) plays a pathophysiologic role in sepsis induced in rat pups by group B streptococci (GBS). In this model, TNF-a is also partially responsible for the induction of interleukin-6 (IL-6). The present study was undertaken to investigate the role of IL-6 in neonatal BALB/c mice infected with type III GBS. The effect of anti-IL-6 monoclonal antibodies and recombinant IL-6 on lethality and TNF-a production was investigated. In mouse pups infected with GBS strain COH1, plasma IL-6 reached levels of 3,067 ± 955 and 1,923 ± 891 U/ml when measured at 22 and 48 h, respectively (P < 0.05 compared with uninfected controls). Pretreatment with 25 ,ug of anti-IL-6 antibodies totally prevented the increase in circulating IL-6 bioactivity at both 22 and 48 h after infection (P < 0.05). Treatment with anti-IL-6 also induced a moderate decrease in survival time of mice infected with lethal doses of strains COHI and COH31, as evidenced by increased lethality (P < 0.05) at 24 to 48 h but not at 96 h. Mouse recombinant IL-6 (12,500 U) given 6 h before challenge with strains COH1 and COH31 consistently increased survival time, as evidenced by decreased (P < 0.05) lethality at 48 to 72 h but not at 96 h. The effects of IL-6 pretreatment were dose dependent, since no protection was observed with doses lower than 12,500 U. In addition, no effects on lethality were noted when II-6 was given at the time of challenge or at later times. TNF-a elevations (P < 0.05 compared with uninfected controls) were measured at 12, 22, and 48 h after challenge with strain COH1 (68 ± 28, 233 + 98, and 98 ± 34 U, respectively). Pretreatment with IL-6 significantly (P < 0.05) decreased plasma TNF-a levels at 12 and 22 h, with 55 and 69%v inhibitions, respectively. Anti-IL-6 had an opposite effect, as evidenced by a 145% increase (P < 0.05) in TNF-a levels at 48 h after challenge. Collectively, our data are compatible with the hypothesis that IL-6 is involved in negative feedback regulation of plasma TNF-a levels in experimental GBS sepsis. In this model, IL-6 pretreatment can increase survival time. Future studies will be needed to investigate the mechanisms underlying this effect.

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Previous studies have indicated that tumor necrosis factor-alpha (TNF-alpha) may play a pathophysiologic role in experimental sepsis by group B streptococci (GBS). We tested the efficacy of some TNF-alpha and eicosanoid inhibitors in a neonatal rat model of GBS disease. The drugs tested included cloricromene, SKF86002, pentoxifylline, CGS8515, ibuprofen and LY203647. None of these compounds were protective against GBS infection, with the exception of pentoxifylline, that produced a moderate enhancement of survival time. Further studies are needed to ascertain if specific inhibitors of TNF-alpha, alone or in conjunction with antibiotics, may be effective as therapeutic agents in neonatal GBS sepsis.

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