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* Department of Neurology, Beth Israel Deaconess Medical Center, Center for Neurodegeneration and Repair, and the Program in Neuroscience,
Channing Laboratory, Brigham and Women’s Hospital, and
Department of Neurology, Children’s Hospital, Harvard Medical School, Boston, MA 02115;
Center for Anatomy, Institute of Cell Biology and Neurobiology, and
¶ Department of Neurology, Charité-Universitaetsmedizin Berlin, Berlin, Germany;
|| Division of Pediatric Infectious Diseases, Children’s Hospital, Albert-Ludwigs-University, Freiburg, Germany; and
# Department of Medicine, University of Massachusetts Medical School, Worcester, MA 01605
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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