Targeting innate immunity to prevent CNS injury in neonatal meningitis

针对先天免疫预防新生儿脑膜炎中枢神经系统损伤

基本信息

批准号：
7244141
负责人：
TIMOTHY VARTANIAN
金额：
$ 18.57万
依托单位：
BETH ISRAEL DEACONESS MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-09-01 至 2008-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7244141
关键词：
Accounting Adaptor Signaling Protein Adjuvant Affect Animals Antibiotic Therapy Antibiotics Apoptosis Apoptotic Astrocytes Bacterial Meningitis Cell Death Cell Surface Receptors Cells Central Nervous System Diseases Cerebral Palsy Cessation of life Clinical Research Clinical Trials Cognitive Critical Care Critical Illness Data Development Developmental Delay Disorders Dexamethasone Disease Event Family Future Gram-Positive Bacteria Heating Hippocampus (Brain)Hydrocephalus Immune Immune response Impairment Infant Infection Infectious Agent Inflammation Inflammatory Inflammatory Response Injury Lead Life Live Birth Mediating Meningitis Microglia Molecular Morbidity - disease rate Mus MyD88 protein Natural Immunity Necrosis Neonatal Nerve Degeneration Neurologic Neuronal Injury Neurons Newborn Infant Oligodendroglia Organism Outcome Pathologic Pathway interactions Patients Pattern recognition receptor Rate Research Personnel Role Seizures Signal Transduction Pathway Standards of Weights and Measures Streptococcus Streptococcus Group B Structure Surface Survivors Testing Therapeutic Agents Time Toll-Like Receptor 2 Toll-like receptors Translational Research Wild Type Mouse Work antimicrobial base central nervous system injury density disability hearing impairment in vitro Model in vivo neocortical neuron loss neurotoxicity novel therapeutics pathogen pre-clinical prevent programs research study response therapeutic target

项目摘要

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.

描述（由申请人提供）：B 族链球菌 (GBS) 是出生第一年细菌性脑膜炎的最常见原因，占所有新生儿脑膜炎病例的近 50%。尽管采用高效的抗菌治疗，新生儿细菌性脑膜炎仍会导致严重的不可逆的认知和身体残疾，从而导致终生损害。我们已经成功开发了体外模型，该模型提供了证据表明，仅当小胶质细胞存在时，用热灭活的 GBS 或 GBS 产生的可溶性因子 (GBS-F) 处理时，皮质神经元才会发生细胞死亡。此外，我们通过证明 GBS 和 GBS-F 介导的小胶质细胞激活需要细胞表面受体 Toll 样受体 2 (TLR2) 和信号传导接头蛋白 MyD88 的功能表达来定义信号转导途径的相关组件。最后，我们确定当小胶质细胞缺乏功能性 TLR2 或 MyDSS 时，不会发生对 GBS 或 GBS-F 的神经毒性反应。我们的初步数据表明革兰氏阳性菌感染、CMS 先天免疫激活和随后的神经变性之间存在因果关系。这些结果支持开发旨在调节小胶质细胞活性的特定疗法作为预防细菌性脑膜炎的神经系统后果的手段的潜力。如果这项转化研究取得积极成果，将导致治疗剂的开发和临床试验。我们的总体假设是，通过 TLR2-MyD88 依赖性机制激活 CMS 中的先天免疫是 GBS 脑膜炎中神经元发生旁观者损伤的原因。我们提出了两个具体目标，使我们能够测试该通路在体内的作用：具体目标 1：确定 GBS（热灭活）介导的先天免疫激活是否会导致神经元损伤，并且是否依赖于体内功能性 TLR2 和 MyD88。假设：将热灭活的 GBS 引入新生小鼠的 CMS 中会导致神经元损伤，并且这种效应将取决于功能性 TLR2 和/或 MyD88 的表达。具体目标 2：确定 GBS（活体）脑膜炎中的神经元损伤是否依赖于功能性 TLR2 和 MyD88。假设：在使用标准抗菌疗法治疗 GBS（活）脑膜炎时，缺乏功能性 TLR2 或 MyD88 的动物的神经元损伤将受到限制。