Potential role of human brain microvascular endothelial cells in the pathogenesis of brain abscess: Inhibition of Staphylococcus aureus by activationof indoleamine 2,3-dioxygenase

Cerebral abscess is a rare complication of staphylococcal septicemia in inf ants associated with high mortality and morbidity. In the pathogenesis of a bscess formation, S. aureus, one major causative agent, interacts with endo thelial cells of the brain vessels before reaching the central nervous syst em. This study examined the growth of S. aureus in human brain microvascula r endothelial cells (HBMEC) cultures stimulated with cytokines. IFN-gamma i nhibited S. aureus replication by the induction of indoleamine 2,3-dioxygen ase (IDO) in HBMEC. This activation of IDO in HBMEC could be shown by RT-PC R and by detection of kynurenine in culture supernatants of activated cells . Resupplementation of L-tryptophan abrogated the inhibitory effect of IFN- gamma on the growth of staphylococci, hence confirming the activation of in doleamine 2,3-dioxygenase as being responsible for the induced bacteriostas is. Addition of TNF-alpha enhanced the IFN-gamma mediated antibacterial eff ects, whereas TNF-alpha alone had no influence on staphylococcal growth. St imulation of HBMEC with IFN-gamma failed to activate inducible nitric oxide synthase (iNOS) and subsequent production of nitric oxide (NO). Thus, intr a- and extracellular depletion of L-tryptophan seems to be an important pro cess in the defense against staphylococcal brain abscesses by means of crea ting an unfavorable microenvironment.