Contribution of tumour necrosis factor-alpha (TNF-α) in host defence mechanism against Cryptococcus neoformans

Abstract

SUMMARYWe investigated the role of TNF-in the host defence mechanism against infection with a virulent strain of Cryptococcus neoformans. Administration of exogenous recombinant human TNF-significantly prolonged the survival time of mice infected by intratracheal instillation of the organism. Surprisingly, neutralizing MoAb to murine TNF-did not shorten their survival time, a finding inconsistent with previous results. To investigate the cause of this inconsistency, we examined the production of TNFin the lungs of infected mice. During the course of cryptococcosis, there was little or no generation of TNF-mRNA in the lung. This might be partly due to a direct inhibitory action of the fungal microorganism on TNF-production by macrophages. In vitro production of TNF-by murine interferon-gamma (IFN-)-and lipopolysaccharide (LPS)-stimulated macrophages was strongly inhibited by co-culturing with the whole yeast cells. In contrast, administration of recombinant murine IL-12 markedly induced TNF-production and the neutralizing anti-TNF-MoAb strongly blocked IL-12-induced protection of mice against cryptococcal infection. These results indicate that endogenously synthesized TNF-has the potential to contribute to the elimination of C. neoformans and partly mediates the protective effect of IL-12.

Induction of Interleukin-12 and Gamma Interferon Requires Tumor Necrosis Factor Alpha for Protective T1-Cell-Mediated Immunity to PulmonaryCryptococcus neoformansInfection

“…Consistent with our current studies, we have previously demonstrated that infection with the highly virulent cryptococcal strain 145A does not induce (i) TNF-␣ or IFN-␥ until later in the infection or (ii) protective T1 immunity (13,29). In addition, Kawakami and colleagues have reported that infection with the highly virulent C. neoformans strain YC-11 does not induce TNF-␣, IL-12, and IFN-␥ (18,19), but treatment of the mice with IL-12 stimulated IFN-␥ production in the lungs and protected them against infection (19).…”

Cryptococcal Urease Promotes the Accumulation of Immature Dendritic Cells and a Non-Protective T2 Immune Response within the Lung

“…8 -10 Quantitative differences in the expression of these factors have been shown to alter the host's ability to clear the primary infection or prevent systemic dissemination. [11][12][13][14][15] However, the specific cellular and molecular mechanisms by which these factors enhance virulence remain largely unknown. Understanding these mechanisms may aid the development of new strategies designed to prevent and/or treat invasive fungal disease in humans.…”

Optimal T Cell Responses to Cryptococcus neoformans Mannoprotein Are Dependent on Recognition of Conjugated Carbohydrates by Mannose Receptors

“…Separation of supernatants by Con A affinity chromatography yields a highly mannosylated protein fraction termed mannoprotein (MP) 3 (14). MP can elicit delayed-type hypersensitivity reactions and induces production of the cytokines TNF-␣ (15), IL-12, and IFN-␥ (16), shown to be critical in decreasing fungal loads in murine models of cryptococcosis (17)(18)(19)(20). Moreover, T cells from patients who have recovered from cryptococcosis proliferate and secrete cytokines in response to MP (21,22).…”