Effect of Deficiency of Tumor Necrosis Factor Alpha or Both of Its Receptors onStreptococcus pneumoniaeCentral Nervous System Infection and Peritonitis

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Abstract
Tumor necrosis factor alpha (TNF-α) and TNF-β are key mediators in bacterial inflammation. We therefore examined the role of TNF-α and its two receptors in murine pneumococcal central nervous system infection. TNF-α knockout mice and age- and sex-matched controls and TNF receptor (p55 and p75)-deficient mice and heterozygous littermates were infected intracerebrally with a Streptococcus pneumoniae type 3 strain. Mice were monitored until death or were killed 36 h after infection. Bacterial titers in blood, spleen, and brain homogenates were determined. Leukocyte infiltration and neuronal damage were assessed by histological scores. TNF-α-deficient mice died earlier than the controls after intracerebral infection although overall survival was similar. TNF-α deficiency did not inhibit leukocyte recruitment into the subarachnoid space and did not lead to an increased density of bacteria in brain homogenates. However, it caused a substantial rise of the concentration of S. pneumoniae cells in blood and spleen. Spleen bacterial titers were also increased in p55- and p75-deficient mice. TNF receptor-deficient mice showed decreased meningeal inflammation. Neuronal damage was not affected by either TNF-α or TNF receptor deficiency. In a murine model of pneumococcal peritonitis, 102 CFU of S. pneumoniaeproduced fatal peritonitis in TNF-α-deficient, but not wild-type, mice. Early leukocyte influx into the peritoneum was impaired in TNF-α-deficient mice. The lack of TNF-α or its receptors renders mice more susceptible to S. pneumoniae infections.