Antimicrobial effects mediated by the regulation of the local tryptophan concentration: diverse effects mediated by different tryptophan degrading enzymes in mice and men
Zusammenfassung der Projektergebnisse
We analyzed the importance of Indoleamine 2,3-dioxygenase (IDO) for the antiparasitic defense against T. gondii in different mammalians within this project. We found that interferon-gamma (IFN-ɣ induced IDO-mediated tryptophan degradation is an important antiparasitic defense mechanism in bovine, porcine and human cells. However, in murine cell cultures IDO is not, or only marginally, induced by IFN-ɣ whereas the inducible nitric oxide synthase (iNOS) and GTPases (IRGs and GBPs) are relevant in the defense against T. gondii. Additional in vivo studies in the mouse system showed that IDO is induced during toxoplasmosis, especially in lung tissue. Detailed analysis proved that the parasite load in the lungs of T. gondii infected IDO-deficient mice is significantly enhanced, indicating that IDO participates in the murine antimicrobial defense T. gondii. In the second part of the project we determined that in addition to IDO, the liver-specific enzyme tryptophan 2,3-dioxygenase (TDO) is also able to mediate antimicrobial effects. Furthermore, we found that TDO can cause immunosuppressive effects and might therefore participate in the creation of the “tolerogenic milieu” in the liver. In the third part of the project we discovered that IDO activity is tightly regulated by factors in the micromilieu. Hence, a reduced availability of oxygen dramatically reduced IDO activity in our in vitro studies. This fits well with our in vivo observation that IDO is especially active in the lung, since the highest oxygene pressure in the body is present in the lung. In addition, we found that an infection of human cells with cytomegalovirus (CMV) results in a profound inhibition of IDO activity. The functional loss of the immunosuppressive IDO activity resulted in an enhanced T cell activation. This might, at least in part, explain the high rejection rate of transplanted organs during active CMV infection.
Projektbezogene Publikationen (Auswahl)
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(2007) Role of indoleamine 2,3-dioxygenase in antimicrobial defence and immunoregulation: tryptophan depletion versus production of toxic kynurenines. Current Drug Metabolism 8: 237-244
MacKenzie CR, Heseler K, Müller A, and Däubener W
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(2008) Antimicrobial and immunoregulatory effects mediated by human lung cells. FEMS 52: 273-281
Heseler K, Stuhlsatz S, Woite C, MacKenzie CR, and Däubener W
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(2009) Antimicrobial and immunoregulatory effector mechanisms in human endothelial cells. Thromb Haemostasis. 102: 1110-1116
Däubener W, Schmidt SK, Heseler K and MacKenzie CR
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(2009) Antimicrobial and immunoregulatory properties of human tryptophan 2,3-dioxygenase. Eur. J Immunol. 29: 275-276
Schmidt SK, Müller A, Heseler K, Woite C, Spekker K, MacKenzie CR, and Däubener W
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(2009) Indoleamine 2,3-dioxygenase is involved in the defense against Neospora caninum in human and bovine cells. Infect Immun., 77: 4496-4501
Spekker K, Czesla M, Ince V, Heseler K, Schmidt SK, Schares G, and Däubener W
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(2009) The missing link between indoleamine 2,3-dioxygenase mediated antibacterial and immunoregulatory effects. J Cell Mol Med. 13: 1125 -1135
Müller A, Heseler K, Schmidt SK, Spekker K, MacKenzie CR, and Däubener W
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(2010) Hypoxia abrogates antichlamydial properties of IFN-γ in human fallopian tube cells in vitro and ex vivo. Proc Nat Acad Sci. 107: 19502-19507
Roth A, König P, van Zandbergen G, Klinger M, Hellwig-Burgel T, Däubener W, Bohlmann MK, and Rupp J
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(2011) Human multipotent mesenchymal stromal cells exhibit broad spectrum antimicrobial effector functions mediated by indoleamine 2,3-dioxygenase. Leukemia. 25: 648-654
Meisel R, Heseler K, Bülle H, Brockers S, Woite C, Stuhlsatz S, Schwippert W, Henschler R, Seissler J, Dilloo D, and Däubener W
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(2012) Influence of tryptophan contained in 1-methyl-tryptophan on antimicrobial and immunoregulatory functions of indoleamine 2,3-dioxygenase. PLoS ONE 7: e44797
Schmidt SK, Siepmann S, Kuhlmann K, Meyer HE, Metzger S, Pudelko S, Leineweber M, and Däubener W
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(2013) Antimicrobial effects of murine mesenchymal stromal cells directed against Toxoplasma gondii and Neospora caninum: Role of immunity-related GTPases (IRGs) and guanylate-binding proteins (GBPs). Med Microb Immunol. 202: 197-206
Spekker K, Leineweber M, Degrandi D, Ince V, Brunder S, Schmidt SK, Stuhlsatz S, Howard JC, Schares G, Degisterici Ö, Meisel R, Sorg RV, Seissler J, Hemphill A, Pfeffer K, and Däubener W
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(2013) Cytomegalovirus impairs the induction of indoleamine 2,3-dioxygenase mediated antimicrobial and immunoregulatory effects in human fibroblasts. PLoS ONE 15: e64442
Heseler K, Schmidt SK, Spekker K, Sinzger C, Sorg RV, Quambusch M, Zimmermann A, Meisel R, and Däubener W
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(2013) Regulation of IDO activity by oxygen supply: inhibitory effects on antimicrobial and immunoregulatory functions. PLoS ONE 13: e63301
Schmidt SK, Ebel S, Keil E, Woite C, Ernst JF, Benzin AE, Rupp J, and Däubener W
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(2014) Checks and balances between human cytomegalovirus replication and indoleamine-2,3-dioxygenase. J Gen Virol. 95: 659-670
Zimmermann A, Hauka S, Maywald M, Le VT, Schmidt SK, Däubener W, and Hengel H
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(2014) Cytomegalovirus infection impairs immunosuppressive and antimicrobial effector functions of human multipotent mesenchymal stromal cells. Mediators Inflamm. 2014: 898630
Meisel R, Heseler K, Nau J, Schmidt SK, Leineweber M, Pudelko S, Wenning J, Zimmermann A, Hengel H, Sinzger C, Degistirici Ö, Sorg RV, and Däubener W
