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组链球菌（GBS）是生命第一年的细菌，脑膜炎的最常见原因，占新生儿脑膜炎病例的近50％。新生儿的细菌性脑膜炎会导致严重的不可逆认知和身体残疾，尽管抗菌治疗高度有效，但仍导致长期损害。我们已经成功地开发了体外建模，该模型提供了证据表明，仅在存在小胶质细胞时，用热灭活的GB或GBS产生的GBS（GBS-F）处理的可溶性因子处理细胞死亡。此外，我们通过表明GBS和GBS-F介导的小胶质细胞激活需要功能表达来定义信号转导途径的相关组件，需要细胞表面受体Toll样受体2（TLR2）和信号衔接子蛋白MyD88。最后，我们确定当小胶质细胞缺乏功能性TLR2或myDs时，对GBS或GBS-F的响应响应于GBS或GBS-F。我们的初步数据表明，革兰氏阳性细菌感染，CMS先天免疫的激活与随后的神经变性之间存在因果关系。这些结果支持开发针对调节小胶质细胞活性的特定疗法的潜力，以防止细菌性脑膜炎的神经系统后果。如果积极的话，这项转化研究将导致治疗剂和临床试验的发展。我们的总体假设是，通过TLR2-MYD88依赖机制激活CMS中的先天免疫力是导致神经元在GBS脑膜炎中发生的旁观者损伤。我们提出了两个具体目标，这些特定目的将使我们能够在体内测试该途径的作用：特定目的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，并依赖于功能性TLR2和MyD88在体内。假设：引入新生儿小鼠CMS的热灭活GB会导致神经元损伤，这种作用将取决于功能性TLR2和或MYD88的表达。具体目的2：确定GBS（活性生物）脑膜炎中的神经元损伤是否取决于功能性TLR2和MYD88。假设：在缺乏功能性TLR2或MYD88的动物中，在接受标准抗菌治疗治疗的GB（活）脑膜炎中，神经元损伤将受到限制。