A mechanism for neurodegeneration induced by group B streptococci through activation of the TLR2/MyD88 pathway in microglia.
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.
Lehnardt
Seija
S
Department of Neurology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
Henneke
Philipp
P
Lien
Egil
E
Kasper
Dennis L
DL
Volpe
Joseph J
JJ
Bechmann
Ingo
I
Nitsch
Robert
R
Weber
Joerg R
JR
Golenbock
Douglas T
DT
Vartanian
Timothy
T
D048868:Adaptor Proteins, Signal Transducing / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D000818:Animals; D017209:Apoptosis / Q000276:immunology; D001253:Astrocytes / Q000276:immunology / Q000378:metabolism; D016923:Cell Death / Q000276:immunology; D002478:Cells, Cultured; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017628:Microglia / Q000276:immunology* / Q000382:microbiology* / Q000473:pathology; D053594:Myeloid Differentiation Factor 88; D019636:Neurodegenerative Diseases / Q000276:immunology* / Q000382:microbiology* / Q000473:pathology; D009474:Neurons / Q000276:immunology / Q000382:microbiology / Q000473:pathology; D009836:Oligodendroglia / Q000276:immunology / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*; D013292:Streptococcus agalactiae / Q000276:immunology*; D051195:Toll-Like Receptor 2 / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics / Q000502:physiology*
D048868:Adaptor Proteins, Signal Transducing; C507780:Myd88 protein, mouse; C507781:Myd88 protein, rat; D053594:Myeloid Differentiation Factor 88; C493486:Tlr2 protein, mouse; D051195:Toll-Like Receptor 2