A Mechanism for Neurodegeneration Induced by Group B Streptococci through Activation of the TLR2/MyD88 Pathway in Microglia
Tóm tắt
Group B Streptococcus (GBS) is a major cause of bacterial meningitis and neurological morbidity in newborn infants. The cellular and molecular mechanisms by which this common organism causes CNS injury are unknown. We show that both heat-inactivated whole GBS and a secreted proteinaceous factor from GBS (GBS-F) induce neuronal apoptosis via the activation of murine microglia through a TLR2-dependent and MyD88-dependent pathway in vitro. Microglia, astrocytes, and oligodendrocytes, but not neurons, express TLR2. GBS as well as GBS-F induce the synthesis of NO in microglia derived from wild-type but not TLR2−/− or MyD88−/− mice. Neuronal death in neuronal cultures complemented with wild-type microglia is NO-dependent. We show for the first time a TLR-mediated mechanism of neuronal injury induced by a clinically relevant bacterium. This study demonstrates a causal molecular relationship between infection with GBS, activation of the innate immune system in the CNS through TLR2, and neurodegeneration. We suggest that this process contributes substantially to the serious morbidity associated with neonatal GBS meningitis and may provide a potential therapeutic target.
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Schuchat, A., M. Oxtoby, S. Cochi. 1990. Population-based risk factors for neonatal group B streptococcal disease: results of a cohort study in Metropolitan Atlanta. J. Infect. Dis. 162: 672-677.
Domingo, P., N. Barquet, M. Alvarez, P. Coll, J. Nava, J. Garau. 1997. Group B streptococcal meningitis in adults: report of twelve cases and review. Clin. Infect. Dis. 25: 1180-1187.
Volpe, J. J.. 2001. Neurology of the Newborn W. B. Saunders, Philadelphia.
de Gans, J., D. van de Beek. 2002. Dexamethasone in adults with bacterial meningitis. N. Engl. J. Med. 347: 1549-1556.
Heath, P. T., G. Balfour, A. M. Weisner, A. Efstratiou, T. L. Lamagni, H. Tighe, L. A. O’Connell, M. Cafferkey, N. Q. Verlander, A. Nicoll, A. C. McCartney. 2004. Group B streptococcal disease in UK and Irish infants younger than 90 days. Lancet 363: 292-294.
Armant, M. A., M. J. Fenton. 2002. Toll-like receptors: a family of pattern-recognition receptors in mammals. Genome Biol. 3: REVIEWS3011
Medzhitov, R., C. A. Janeway, Jr. 1999. Innate immune induction of the adaptive immune response. Cold Spring Harb. Symp. Quant. Biol. 64: 429-435.
Kawai, T., O. Takeuchi, T. Fujita, J. Inoue, P. F. Muhlradt, S. Sato. 2001. Lipopolysaccharide stimulates the MyD88-independent pathway and results in activation of IRF-3 and the expression of a subset of LPS-inducible genes. J. Immunol. 167: 5887-5894.
Fitzgerald, K. A., E. M. Palsson-McDermott, A. G. Bowie, C. Jefferies, A. S. Mansell, G. Brady. 2001. Mal (MyD88-adaptor-like) is required for Toll-like receptor-4 signal transduction. Nature 413: 78-83.
Yamamoto, M., S. Sato, H. Hemmi, K. Hoshino, T. Kaisho, H. Sanjo, O. Takeuchi, M. Sugiyama, M. Okabe, K. Takeda, S. Akira. 2003. Role of adaptor TRIF in the MyD88-independent Toll-like receptor signaling pathway. Science 301: 640-643.
Yamamoto, M., S. Sato, H. Hemmi, S. Uematsu, K. Hoshino, T. Kaisho, O. Takeuchi, K. Takeda, S. Akira. 2003. TRAM is specifically involved in the Toll-like receptor 4-mediated MyD88-independent signaling pathway. Nat. Immunol. 4: 1144-1150.
Yoshimura, A., E. Lien, R. R. Ingalls, E. Tuomanen, R. Dziarski, D. Golenbock. 1999. Cutting edge: recognition of Gram-positive bacterial cell wall components by the innate immune system occurs via Toll-like receptor 2. J. Immunol. 163: 1-5.
Underhill, D. M., A. Ozinsky, A. M. Hajjar, A. Stevens, C. B. Wilson, M. Bassetti, A. Aderem. 1999. The Toll-like receptor 2 is recruited to macrophage phagosomes and discriminates between pathogens. Nature 401: 811-815.
Takeuchi, O., K. Hoshino, T. Kawai, H. Sanjo, H. Takada, T. Ogawa, K. Takeda, S. Akira. 1999. Differential roles of TLR2 and TLR4 in recognition of Gram-negative and Gram-positive bacterial cell wall components. Immunity 11: 443-451.
Takeuchi, O., A. Kaufmann, K. Grote, T. Kawai, K. Hoshino, M. Morr, P. F. Muhlradt, S. Akira. 2000. Cutting edge: preferentially the R-stereoisomer of the mycoplasmal lipopeptide macrophage-activating lipopeptide-2 activates immune cells through a Toll-like receptor 2- and MyD88-dependent signaling pathway. J. Immunol. 164: 554-557.
Schwandner, R., R. Dziarski, H. Wesche, M. Rothe, C. J. Kirschning. 1999. Peptidoglycan- and lipoteichoic acid-induced cell activation is mediated by Toll-like receptor 2. J. Biol. Chem. 274: 17406-17409.
Weber, J. R., D. Freyer, C. Alexander, N. W. Schröder, A. Reiss, C. Küster, D. Pfeil, E. I. Tuomanen, R. R. Schumann. 2003. Recognition of pneumococcal peptidoglycan: an expanded, pivotal role for LPS binding protein. Immunity 19: 269-279.
Ozinsky, A., D. M. Underhill, J. D. Fontenot, A. M. Hajjar, K. D. Smith, C. B. Wilson, L. Schroeder, A. Aderem. 2000. The repertoire for pattern recognition of pathogens by the innate immune system is defined by cooperation between Toll-like receptors. Proc. Natl. Acad. Sci. USA 97: 13766-13771.
Laflamme, N., G. Soucy, S. Rivest. 2001. Circulating cell wall components derived from Gram-negative, not Gram-positive, bacteria cause a profound induction of the gene-encoding Toll-like receptor 2 in the CNS. J. Neurochem. 79: 648-657.
Henneke, P., O. Takeuchi, J. A. van Strijp, H.-K. Guttormsen, J. A. Smith, A. B. Schromm, T. A. Espevik, S. Akira, V. Nizet, D. L. Kasper, D. T. Golenbock. 2001. Novel engagement of CD14 and multiple Toll-like receptors by group B streptococci. J. Immunol. 167: 7069-7076.
Mancuso, G., A. Midiri, C. Beninati, C. Biondo, R. Galbo, S. Akira, P. Henneke, D. Golenbock, G. Teti. 2004. Dual role of TLR2 and myeloid differentiation factor 88 in a mouse model of invasive group B streptococcal disease. J. Immunol. 172: 6324-6329.
Lehnardt, S., C. Lachance, S. Patrizi, S. Lefebvre, P. L. Follett, F. E. Jensen, P. A. Rosenberg, J. J. Volpe, T. Vartanian. 2002. The Toll-like receptor TLR4 is necessary for lipopolysaccharide-induced oligodendrocyte injury in the CNS. J. Neurosci. 22: 2478-2486.
Lehnardt, S., L. Massillon, P. Follett, F. E. Jensen, R. Ratan, P. A. Rosenberg, J. J. Volpe, T. Vartanian. 2003. Activation of innate immunity in the CNS triggers neurodegeneration through a Toll-like receptor 4-dependent pathway. Proc. Natl. Acad. Sci. USA 100: 8514-8519.
Henneke, P., S. Morath, S. Uematsu, S. Weichert, M. Pfitzenmaier, O. Takeuchi, A. Müller, C. Poyart, S. Akira, R. Berner, et al 2005. Role of lipoteichoic acid in the phagocyte response to Group B Streptococcus. J. Immunol. 174: 6449-6455.
Vartanian, T., Y. Li, M. Zhao, K. Stefansson. 1995. Interferon-γ-induced oligodendrocyte cell death: implications for the pathogenesis of multiple sclerosis. Mol. Med. 1: 732-743.
Chen, W., U. Syldath, K. Bellmann, V. Burkart, H. Kolb. 1999. Human 60-kDa heat-shock protein: a danger signal to the innate immune system. J. Immunol. 162: 3212-3219.
Nilsen, N., U. Nonstad, N. Khan, C. F. Knetter, S. Akira, A. Sundan, T. Espevik, E. Lien. 2004. Lipopolysaccharide and double-stranded RNA up-regulate Toll-like receptor 2 independently of myeloid differentiation factor 88. J. Biol. Chem. 279: 39727-39735.
Lien, E., T. J. Sellati, A. Yoshimura, T. H. Flo, G. Rawadi, R. W. Finberg, J. D. Carroll, T. Espevik, R. R. Ingalls, J. D. Radolf, D. T. Golenbock. 1999. Toll-like receptor 2 functions as a pattern recognition receptor for diverse bacterial products. J. Biol. Chem. 274: 33419-33425.
Lien, E., T. K. Means, H. Heine, A. Yoshimura, S. Kusumoto, K. Fukase, M. J. Fenton, M. Oikawa, N. Qureshi, B. Monks, et al 2000. Toll-like receptor 4 imparts ligand-specific recognition of bacterial lipopolysaccharide. J. Clin. Invest. 105: 497-504.
Neuhaus, F. C., J. Baddiley. 2003. A continuum of anionic charge: structures and functions of d-alanyl-teichoic acids in Gram-positive bacteria. Microbiol. Mol. Biol. Rev. 67: 686-723.
Leib, S. L., Y. S. Kim, L. L. Chow, R. A. Sheldon, M. G. Tauber. 1996. Reactive oxygen intermediates contribute to necrotic and apoptotic neuronal injury in an infant rat model of bacterial meningitis due to group B streptococci. J. Clin. Invest. 98: 2632-2639.
Tauber, M. G., Y. S. Kim, S. L. Leib. 1997. Defense of the Brain: Current Concepts in the Immunopathogenesis and Clinical Aspects of CNS Infections Blackwell Science, Malden.
Braun, J. S., J. E. Sublett, D. Freyer, T. J. Mitchell, J. L. Cleveland, E. I. Tuomanen, J. R. Weber. 2002. Pneumococcal pneumolysin and H2O2 mediate brain cell apoptosis during meningitis. J. Clin. Invest. 109: 19-27.
Braun, J. S., R. Novak, K. H. Herzog, S. M. Bodner, J. L. Cleveland, E. I. Tuomanen. 1999. Neuroprotection by a caspase inhibitor in acute bacterial meningitis. Nat. Med. 5: 298-302.
Flo, T. H., Ø. Halaas, E. Lien, L. Ryan, G. Teti, D. T. Golenbock, A. Sundan, T. Espevik. 2000. Human Toll-like receptor 2 mediates monocyte activation by Listeria monocytogenes, but not by group B streptococci or lipopolysaccharide. J. Immunol. 164: 2064-2069.
Brightbill, H. D., D. H. Libraty, S. R. Krutzik, R.-B. Yang, J. T. Belisle, J. R. Bleharski, M. Maitland, M. V. Norgard, S. E. Plevy, S. T. Smale, et al 1999. Host defense mechanisms triggered by microbial lipoproteins through Toll-like receptors. Science 285: 732-736.
Koedel, U., B. Angele, T. Rupprecht, H. Wagner, A. Roggenkamp, H. W. Pfister, C. J. Kirschning. 2003. Toll-like receptor 2 participates in mediation of immune response in experimental pneumococcal meningitis. J. Immunol. 170: 438-444.
Bsibsi, M., R. Ravid, D. Gveric, J. M. van Noort. 2002. Broad expression of Toll-like receptors in the human central nervous system. J. Neuropathol. Exp. Neurol. 61: 1013-1021.
Kielian, T., N. Esen, E. D. Bearden. 2005. Toll-like receptor 2 (TLR2) is pivotal for recognition of S. aureus peptidoglycan but not intact bacteria by microglia. Glia 49: 567-576.
Kawai, T., O. Adachi, T. Ogawa, K. Takeda, S. Akira. 1999. Unresponsiveness of MyD88-deficient mice to endotoxin. Immunity 11: 115-122.
Medzhitov, R., P. Preston-Hurlburt, E. Kopp, A. Stadlen, C. Chen, S. Ghosh, C. A. Janeway, Jr. 1998. MyD88 is an adaptor protein in the hToll/IL-1 receptor family signaling pathways. Mol. Cell 2: 253-258.
Chao, C. C., S. Hu, T. W. Molitor, E. G. Shaskan, P. K. Peterson. 1992. Activated microglia mediate neuronal cell injury via a nitric oxide mechanism. J. Immunol. 149: 2736-2741.
Brosnan, C. F., L. Battistini, C. S. Raine, D. W. Dickson, A. Casadevall, S. C. Lee. 1994. Reactive nitrogen intermediates in human neuropathology: an overview. Dev. Neurosci. 16: 152-161.
Poltorak, A., X. He, I. Smirnova, M.-Y. Liu, C. Van Huffel, X. Du, D. Birdwell, E. Alejos, M. Silva, C. Galanos, et al 1998. Defective LPS signaling in C3H/HeJ and C57BL/10ScCr mice: mutations in Tlr4 gene. Science 282: 2085-2088.
Qureshi, S. T., L. Larivière, G. Leveque, S. Clermont, K. J. Moore, P. Gros, D. Malo. 1999. Endotoxin-tolerant mice have mutations in Toll-like receptor 4 (Tlr4). J. Exp. Med. 189: 615-625.
Hoshino, K., O. Takeuchi, T. Kawai, H. Sanjo, T. Ogawa, Y. Takeda, K. Takeda, S. Akira. 1999. Cutting edge: Toll-like receptor 4 (TLR4)-deficient mice are hyporesponsive to lipopolysaccharide: evidence for TLR4 as the Lps gene product. J. Immunol. 162: 3749-3752.
Schuchat, A., K. Robinson, J. D. Wenger, L. H. Harrison, M. Farley, A. L. Reingold, L. Lefkowitz, B. A. Perkins. 1997. Bacterial meningitis in the United States in 1995: Active Surveillance Team. N. Engl. J. Med. 337: 970-976.
Edwards, M. S., M. A. Rench, A. A. Haffar, M. A. Murphy, M. M. Desmond, C. J. Baker. 1985. Long-term sequelae of group B streptococcal meningitis in infants. J. Pediatr. 106: 717-722.
Bermpohl, D., A. Halle, D. Freyer, E. Dagand, J. S. Braun, I. Bechmann, N. W. Schroder, J. R. Weber. 2005. Bacterial programmed cell death of cerebral endothelial cells involves dual death pathways. J. Clin. Invest. 115: 1607-1615.
Leib, S. L., M. G. Tauber. 1999. Pathogenesis of bacterial meningitis. Infect. Dis. Clin. North. Am. 13: 527-548.
Bogdan, I., S. L. Leib, M. Bergeron, L. Chow, M. G. Tauber. 1997. Tumor necrosis factor-α contributes to apoptosis in hippocampal neurons during experimental group B streptococcal meningitis. J. Infect. Dis. 176: 693-697.
Nau, R., A. Soto, W. Bruck. 1999. Apoptosis of neurons in the dentate gyrus in humans suffering from bacterial meningitis. J. Neuropathol. Exp. Neurol. 58: 265-274.
Henneke, P., O. Takeuchi, R. Malley, E. Lien, R. R. Ingalls, M. W. Freeman, T. Mayadas, V. Nizet, S. Akira, D. L. Kasper, D. T. Golenbock. 2002. Cellular activation, phagocytosis, and bactericidal activity against Group B Streptococcus involve parallel myeloid differentiation factor 88-dependent and independent signaling pathways. J. Immunol. 169: 3970-3977.
Peterson, J. W., L. Bo, S. Mork, A. Chang, R. M. Ransohoff, B. D. Trapp. 2002. VCAM-1-positive microglia target oligodendrocytes at the border of multiple sclerosis lesions. J. Neuropathol. Exp. Neurol. 61: 539-546.
Liu, B., J. S. Hong. 2003. Role of microglia in inflammation-mediated neurodegenerative diseases: mechanisms and strategies for therapeutic intervention. J. Pharmacol. Exp. Ther. 304: 1-7.
Grangette, C., S. Nutten, E. Palumbo, S. Morath, C. Hermann, J. Dewulf, B. Pot, T. Hartung, P. Hols, A. Mercenier. 2005. From the cover: enhanced antiinflammatory capacity of a Lactobacillus plantarum mutant synthesizing modified teichoic acids. Proc. Natl. Acad. Sci. USA 102: 10321-10326.
Morath, S., A. Stadelmaier, A. Geyer, R. R. Schmidt, T. Hartung. 2002. Synthetic lipoteichoic acid from Staphylococcus aureus is a potent stimulus of cytokine release. J. Exp. Med. 195: 1635-1640.
Aliprantis, A. O., R. B. Yang, M. R. Mark, S. Suggett, B. Devaux, J. D. Radolf, G. R. Klimpel, P. Godowski, A. Zychlinsky. 1999. Cell activation and apoptosis by bacterial lipoproteins through Toll-like receptor-2. Science 285: 736-739.
Oliveira, R. B., M. T. Ochoa, P. A. Sieling, T. H. Rea, A. Rambukkana, E. N. Sarno, R. L. Modlin. 2003. Expression of Toll-like receptor 2 on human Schwann cells: a mechanism of nerve damage in leprosy. Infect. Immun. 71: 1427-1433.
Into, T., Y. Nodasaka, A. Hasebe, T. Okuzawa, J. Nakamura, N. Ohata, K. Shibata. 2002. Mycoplasmal lipoproteins induce Toll-like receptor 2- and caspases-mediated cell death in lymphocytes and monocytes. Microbiol. Immunol. 46: 265-276.
Morr, M., O. Takeuchi, S. Akira, M. M. Simon, P. F. Muhlradt. 2002. Differential recognition of structural details of bacterial lipopeptides by Toll-like receptors. Eur. J. Immunol. 32: 3337-3347.
Sutcliffe, I. C., D. J. Harrington. 2002. Pattern searches for the identification of putative lipoprotein genes in Gram-positive bacterial genomes. Microbiology 148: 2065-2077.
Liu, G. Y., K. S. Doran, T. Lawrence, N. Turkson, M. Puliti, L. Tissi, V. Nizet. 2004. Sword and shield: linked group B streptococcal β-hemolysin/cytolysin and carotenoid pigment function to subvert host phagocyte defense. Proc. Natl. Acad. Sci. USA 101: 14491-14496.
Pavlov, V. A., H. Wang, C. J. Czura, S. G. Friedman, K. J. Tracey. 2003. The cholinergic anti-inflammatory pathway: a missing link in neuroimmunomodulation. Mol. Med. 9: 125-134.
Czura, C. J., S. G. Friedman, K. J. Tracey. 2003. Neural inhibition of inflammation: the cholinergic anti-inflammatory pathway. J. Endotoxin Res. 9: 409-413.
Wyss-Coray, T., L. Mucke. 2002. Inflammation in neurodegenerative disease: a double-edged sword. Neuron 35: 419-432.
Zekki, H., D. L. Feinstein. 2002. The clinical course of experimental autoimmune encephalomyelitis is associated with a profound and sustained transcriptional activation of the genes encoding Toll-like receptor 2 and CD14 in the mouse CNS. Brain Pathol. 12: 308-319.