Targeting innate immunity to prevent CNS injury in neonatal meningitis

Beth Israel Deaconess Medical Center, Boston MA

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Abstract

[unreadable] DESCRIPTION (provided by applicant): Group B streptococcus (GBS) is the most common cause of bacterial, meningitis in the first year of life and accounts for nearly 50% of all cases of neonatal meningitis. Bacterial meningitis in newborn infants causes severe irreversible cognitive and physical disability resulting in life long impairment despite highly effective antimicrobial therapy. We have successfully developed in vitro modeling which provides evidence that cortical neurons undergo cell death when treated with heat-inactivated GBS or a soluble factor produced by GBS (GBS-F) only when microglia are present. Furthermore, we defined relevant components of the signal transduction pathway by showing that both GBS and GBS-F mediated activation of microglia require functional expression the cell surface receptor toll-like receptor 2 (TLR2) and the signaling adaptor protein MyD88. Finally, we established that the neurotoxicity in response to GBS or GBS-F failed to occur when microglia lacked functional TLR2 or MyDSS. Our preliminary data suggest a causal relationship between infection with gram-positive bacteria, activation of CMS innate immunity, and subsequent neurodegeneration. These results support the potential for development of specific therapies directed towards modulating microglial activity as a means of preventing the neurological consequences of bacterial meningitis. This translational research, if positive, will then lead to development of a therapeutic agent and clinical trial. Our overall hypothesis is that activation of innate immunity in the CMS through a TLR2-MyD88 dependent mechanism is responsible for the bystander injury that occurs to neurons in the setting of GBS meningitis. We propose two specific aims that will allow us to test the role of this pathway in vivo: Specific Aim 1: To determine if GBS (heat inactivated) mediated activation of innate immunity causes neuronal injury and is dependent on functional TLR2 and MyD88 in vivo. Hypothesis: Heat inactivated GBS introduced into the CMS of neonatal mice will cause neuronal injury and this effect will be dependent on expression of functional TLR2 and or MyD88. Specific Aim 2: To determine if neuronal injury in GBS (live organism) meningitis is dependent upon functional TLR2 and MyD88. Hypothesis: In GBS (live) meningitis treated with standard antimicrobial therapy, neuronal injury will be limited in animals lacking functional TLR2 or MyD88. [unreadable] [unreadable] [unreadable]