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.

S. aureus - HBMEC - IDO - Tryptophan - IFN-γ

References

• 1 Abdelnour A, Tarkowski A. Polyclonal B-cell activation by an arthritogenic Staphylococcus aureus strain: contribution of T cells and monokines.  Cell Immunol. 1993;  147 279-293
• 2 Aebi C, Kaufmann F, Schaad U B. Brain abscess in childhood - long-term experiences.  Eur J Pediatr. 1991;  150 282-286
• 3 Bakhiet M, Mustafa M, Zhu J, Harris R, Lindquist L, Link H, Diab A. Induction of cytokines and anti-cytokine autoantibodies in cerebrospinal fluid (CSF) during experimental bacterial meningitis.  Clin Exp Immunol. 1998;  114 398-402
• 4 Beekhuizen H, van de Gevel J S, Olsson B, van Benten I J, van Furth R. Infection of human vascular endothelial cells with Staphylococcus aureus induces hyperadhesiveness for human monocytes and granulocytes.  J Immunol. 1997;  158 774-782
• 5 Boelens J J, van der Poll T, Dankert J, Zaat S A. Interferon-gamma protects against biomaterial-associated Staphylococcus epidermidis infection in mice.  J Infect Dis. 2000;  181 1167-1171
• 6 Brook I. Brain abscess in children: Microbiology and management.  J Child Neurol. 1995;  10 283-288
• 7 Ciurea A V, Stoica F, Vasilescu G, Nuteanu L. Neurosurgical management of brain abscesses in children.  Child's Nerv Syst. 1999;  15 309-317
• 8 Cochrane D D. Consultation with the specialist. Brain abscess.  Pediatr Rev. 1999;  20 209-215
• 9 Däubener W, Remscheid C, Nockemann S, Pilz K, Seghrouchni S, MacKenzie C, Hadding U. Anti parasitic effector mechanisms in human brain tumor cells: role of interferon-γ and tumor necrosis factor-α.  Eur J Immunol. 1996;  26 487-492
• 10 Däubener W, Hucke C, Seidel K, Hadding U, MacKenzie C. Interleukin-1 inhibits gamma interferon-induced bacteriostasis in human uroepithelial cells.  Infect Immun. 1999;  67 5615-5620
• 11 Ding A H, Nathan C F, Stuehr D J. Release of reactive nitrogen intermediates and reactive oxygen intermediates from mouse peritoneal macrophages. Comparison of activating cytokines and evidence for independent production.  J Immunol. 1988;  141 2407-2412
• 12 Fleischer B, Gerlach D, Fuhrmann A, Schmidt K H. Superantigens and pseudosuperantigens of Gram-positive cocci.  Med Microbiol Immunol. 1995;  184 1-8
• 13 Freeden v U, Zessack N, van Valen F, Burdach S. Defective interferon gamma production in neonatal T cells is independent of interleukin-2 receptor binding.  Pediatr Res. 1991;  30 270-275
• 14 Jonson S C, Kazzi N J. Candida brain abscess: a sonographic mimicker of intracranial hemorrhage.  J Ultrasound Med. 1993;  4 237-239
• 15 Kagawa M, Takeshita M, Yato S, Kitamura K. Brain abscess in congenital heart disease.  J Neurosurg. 1983;  58 913-917
• 16 Leist T P, Frei K, Kam-Hansen S, Zinkernagel R M, Fontana A. Tumor necrosis factor-α in cerebrospinal fluid during bacterial, but not viral meningitis. Evaluation in murine model infections and in patients.  J Exp Med. 1988;  167 1743-1748
• 17 Lowy F D, Fant J, Higgins L L, Ogawa S K, Hatcher V B. Staphylococcus aureus-human endothelial cell interactions.  J Ultrastruct Mol Struct Res. 1988;  98 137-146
• 18 MacKenzie C R, Willberg C B, Däubener W. Inhibition of group B streptococcal growth by IFN-γ-activated human glioblastoma cells.  J Neuroimmunol. 1998;  89 191-197
• 19 MacKenzie C R, Hadding U, Däubener W. Interferon-γ-induced activation of indoleamine 2, 3-dioxygenase in cord blood monocyte-derived macrophages inhibits the growth of group B streptococci.  J Infect Dis. 1998;  178 875-878
• 20 Mathisen G E, Johnson J P. Brain abscess.  CID. 1997;  25 763-781
• 21 Nakane A, Okamoto M, Asano M, Kohanawa M, Minagawa T. Endogenous gamma interferon, tumor necrosis factor, and interleukin-6 in Staphylococcus aureus infection in mice.  Infect Immun. 1995;  63 1165-1172
• 22 Nielsen H. Cerebral abscess in children.  Neuropediatrics. 1983;  14 76-80
• 23 Ohga S, Aoki T, Okada K, Akeda H, Fujioka K, Ohshima A, Mori T, Minamishima I, Ueda K. Cerebrospinal fluid concentrations of interleukin-1 beta, tumor necrosis factor-alpha, and interferon gamma in bacterial meningitis.  Arch Dis Child. 1994;  70 123-125
• 24 Pfefferkorn E R. Interferon-γ blocks the growth of Toxoplasma gondii in human fibroblasts by inducing the host cells to degrade tryptophan.  Proc Natl Acad Sci USA. 1984;  81 908-912
• 25 Proctor R A, van Langevelde P, Kristjansson M, Maslow J N, Arbeit R D. Persistent and relapsing infections associated with small-colony variants of Staphylococcus aureus. .  Clin Infect Dis. 1995;  20 95-102
• 26 Saez-Llorens X J, Umana M A, Odio C M, McCracken G H, Nelson J D. Brain abscess in infants and children.  Pediatr Infect Dis J. 1989;  8 449-458
• 27 Sakiniene E, Bremell T, Tarkowski A. Inhibition of nitric oxide synthase (NOS) aggravates Staphylococcus aureus septicaemia and septic arthritis.  Clin Exp Immunol. 1997;  110 370-377
• 28 Scott M E, Kubin M, Kohl S. High level interleukin-12 production, but diminished interferon-γ production, by cord blood mononuclear cells.  Pediatr Res. 1997;  41 547-553
• 29 Soderquist B, Kallman J, Holmberg H, Vikerfors T, Kihlstrom E. Secretion of IL-6, IL-8 and G-CSF by human endothelial cells in vitro in response to Staphylococcus aureus and staphylococcal exotoxins.  APMIS. 1998;  106 1157-1164
• 30 Stins M, Gilles F, Kim K S. Selective expression of adhesion molecules on human brain microvascular endothelial cells.  J Neuroimmun. 1997;  76 81-90
• 31 Takeshita M, Kagawa M, Yato S, Izawa M, Onda H, Takakura K, Momma K. Current treatment of brain abscess in patients with congenital cyanotic heart disease.  Neurosurgery. 1997;  41 1270-1278
• 32 Woods C R. Brain abscess and other intracranial suppurative complications.  Adv Pediatr Infect Dis. 1995;  10 41-79
• 33 Zhao Y X, Ljungdahl A, Olsson T, Tarkowski A. In situ hybridization analysis of synovial and systemic cytokine messenger RNA expression in superantigen-mediated Staphylococcus aureus arthritis.  Arthritis Rheum. 1996;  39 959-967
• 34 Zhao Y X, Nilsson I M, Tarkowski A. The dual role of interferon-γ in experimental Staphylococcus aureus septicaemia versus arthritis.  Immunology. 1998;  93 80-85