ROLE OF TUMOR-NECROSIS-FACTOR-ALPHA AND INTERFERON-GAMMA IN NEWBORN HOST DEFENSE AGAINST LISTERIA-MONOCYTOGENES INFECTION

The fetus and newborn are particularly susceptible to Listeria monocytogenes infection. We used a newborn rat animal model to investigate neonatal host defense against Listeria. In this animal model, newborn (3-d-old) rats are more susceptible to L. monocytogenes than older animals. Juvenile (23-d-old) L. monocytogenes-infected rats pretreated with lipopolysaccharide (LPS) had a lower bacterial load in blood than control animals, whereas LPS pretreated newborn rats had a higher bacterial load. Because LPS is a potent inducer of tumor necrosis factor (TNF) and TNF enhances host defense against this organism in adult animals, we assessed TNF content in splenic homogenates for animals of different ages. The age at which TNF was detectable in L. monocytogenes-Infected rats corresponded to the age at which LPS became active in preventing severe bacteremia. TNF was less than 1 unit/mL in splenic homogenates taken from rats less than 8 d of age, whereas 16-d-old rats infected with L. monocytogenes 1 d earlier had greater than 80 units/mL (p < 0.0001 for 3-d-old versus 16-d-old rats). We also assessed the responsiveness of rats to exogenous TNF-alpha. Juvenile rats pretreated with TNF-alpha before L. monocytogenes infection had decreased bacterial load in spleen (p < 0.02 versus controls) and better survival at 7 d (p < 0.05 versus controls), whereas newborn rats did not improve with TNF-alpha pretreatment (p > 0.05 treated versus controls for splenic bacterial load and 7-d survival). However, when newborn rats were pretreated with both interferon-gamma (IFN-gamma) and TNF-alpha, splenic bacterial content was decreased compared to animals pretreated with PBS, IFN-gamma, or TNF-alpha alone (p < 0.005 combination versus TNF-alpha, IFN-gamma, or PBS). Similarly, survival also was improved for newborn rats pretreated with both IFN-gamma and TNF-alpha compared to controls pretreated with either of these agents alone (p < 0.02 combination versus control, p > 0.05 TNF-alpha or IFN-gamma versus controls). We conclude that TNF production is decreased among newborn rats challenged with L. monocytogenes compared to TNF production in older animals. TNF-alpha does not enhance resistance of newborn rats to L. monocytogenes unless they are pretreated with IFN-gamma as well.