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

Cerebral abscess is a rare complication of staphylococcal septicemia in infants associated with high mortality and morbidity. In the pathogenesis of abscess formation, S. aureus, one major causative agent, interacts with endothelial cells of the brain vessels before reaching the central nervous system. This study examined the growth of S. aureus in human brain microvascular endothelial cells (HBMEC) cultures stimulated with cytokines. IFN-γ inhibited S. aureus replication by the induction of indoleamine 2,3-dioxygenase (IDO) in HBMEC. This activation of IDO in HBMEC could be shown by RT-PCR and by detection of kynurenine in culture supernatants of activated cells. Resupplementation of L-tryptophan abrogated the inhibitory effect of IFN-γ on the growth of staphylococci, hence confirming the activation of indoleamine 2,3-dioxygenase as being responsible for the induced bacteriostasis. Addition of TNF-α enhanced the IFN-γ mediated antibacterial effects, whereas TNF-α alone had no influence on staphylococcal growth, Stimulation of HBMEC with IFN-γ failed to activate inducible nitric oxide synthase (iNOS) and subsequent production of nitric oxide (NO). Thus, intra- and extracellular depletion of L-tryptophan seems to be an important process in the defense against staphylococcal brain abscesses by means of creating an unfavorable microenvironment.