Tumor necrosis factor alpha has a protective role in a murine model of systemic candidiasis

Abstract

The role of tumor necrosis factor alpha (TNF-a) in host defense against systemic Candida albicans infection was evaluated in a murine model of systemic candidiasis in which uniform death occurred between 5 and 6 days after infection. TNF-a was first detected at 16 h postinfection and progressively increased thereafter. Peak levels (700 to 900 pg/ml) were measured in mice near death. Administration of 0.5 to 1.0 mg of polyclonal immunoglobulin G (IgG) TNF-oa antibody (TNF-ax Ab) to mice 2 h preinfection neutralized serum TNF-a for up to 30 h. However, this regimen shortened survival from a mean of 5.5 days for IgG controls to 3.4 days (P = 1.9 x 10-12). Semiquantitative cultures of spleen, lung, liver, and kidney conducted at 1, 2, and 3 days postinfection found colony counts of spleen and kidney to be significantly higher for TNF-aL Ab recipients but only for the first 48 h. Administration of 1.5 and 1.0 mg of TNF-ea Ab at 2 h before and 48 h after fungal injection, respectively, shortened the mean survival from 4.9 to 2.3 days (P = 5.2 x 10-8). This regimen neutralized serum TNF-a throughout infection. With this regimen, colony counts of all organs were significantly higher in TNF-a Ab recipients at 1, 2, and 3 days postinfection. Histopathologic studies showed an increase in the number and size of C. albicans foci in tissues. Peripheral leukocyte counts and inflammatory response in tissue were similar for TNF-a Ab and IgG sham recipients. In vitro, incubation of C. albicans with four to eight times the peak serum levels of TNF-c for up to 24 h did not inhibit the rate of germ tube or pseudohypha formation. Thus, TNF-aL that was produced during infection with C. albicans augmented host resistance against this organism and prolonged survival. The protective effect of TNF-a was not mediated by increased leukocytes in blood or tissues nor by a direct anticandidal effect of TNF-ai. This study suggests that the administration of exogenous TNF-a may enhance host resistance against systemic C. albicans infection and may improve host survival.

Impairment of p38 MAPK‐mediated cytosolic phospholipase A2 activation in the kidneys is associated with pathogenicity of Candida albicans

“…33,34 Thus, the importance of NF-jB activity in C. albicans infection is based on its capacity to induce anticandidal cytokines such as TNF-a, IL-1 and granulocyte colony-stimulating factor. [35][36][37] Among these cytokines, we have found that TNF-a is the key effectors molecule in protection against C. albicans. 12,13 Our unpublished recent finding showing that non-pathogenic C. albicans became pathogenic in TNF-a knockout mice, further establishes the importance of this cytokine in C. albicans clearance.…”

Modulation of neutrophil function in host defense against disseminated Candida albicans infection in mice

“…The pro-in£ammatory cytokine tumor necrosis factor-K (TNFK) is also induced by Candida mannoproteins in vitro [14]. Its requirement for the host defense has become clear from experiments in which treatment of mice with monoclonal antibodies against TNFK enhances the mortality to experimental disseminated candidiasis [15,22]. Likewise, treatment with pharmacological inhibitors of TNFK production leads to enhanced mortality and increased outgrowth of C. albicans during disseminated candidiasis in mice [23].…”

Effects of macrophage colony-stimulating factor (M-CSF) on anti-fungal activity of mononuclear phagocytes againstTrichosporon asahii

“…The role of TNF-a in this infection was further demonstrated in experiments using anti-TNF-a antibody; the administration of the antibody markedly reduced the survival rate. Louie et al [25] described that the administration of TNF-a antibody in a murine model of systemic candidiasis neutralized serum TNF-a, shortened survival, and increased fungal colony counts in the spleen, kidney, liver and lung. Nagai et al [20] also reported that TNF-a exhibits a protective role in invasive aspergillosis.…”