Inflammatory mediators and neurodevelopmental morbidity associated with invasive Group B Streptococcus (GBS) disease early in life.

在发达国家和发展中国家，新生儿败血症的一个重要原因是无乳链球菌或B族链球菌（GBS），一种革兰氏阳性β-溶血性、包囊双球菌。妊娠相关GBS定植可能导致婴儿侵袭性GBS疾病（iGBS），包括脑膜炎或败血症，具有高死亡风险。据估计，2015年3个月以下婴儿中有319，000例侵袭性GBS病例，其中90，000例是致命的，另外10，000例主要继发于GBS脑膜炎的中度至重度神经功能障碍。 此外，最近的研究强调，不良的NDI结果也延伸到iGBS败血症的幸存者。在与新生儿GBS病有关的估计死亡率和发病率中，一半以上在非洲。为了降低新生儿GBS疾病的发病率，重要的是要了解疾病的长期后果。目前缺乏关于新生儿GBS感染的长期结局（如神经发育障碍）的信息。结合长期发病率和死亡率结果，这些数据对于更详细地评估疾病负担和评估经济负担特别重要。因此，项目A的目的是进一步调查南非和莫桑比克新生儿或婴儿侵袭性疾病（iGBS）幸存儿童的神经发育障碍（NDI）和社会情绪行为的风险。对于项目B，我们还将测量iGBS疾病引起的长期健康相关生活质量和经济成本。由GBS和细菌本身引起的急性炎症反应，最有可能导致神经功能障碍。因此，为了补充评估iGBS幸存者中的NDI的基于人类的研究，我们旨在进行表征iGBS幸存者中的免疫应答的研究（项目C）。与研究新生儿对iGBS疾病的免疫应答的人体研究一致，我们还旨在进行一系列体外和体内动物研究，旨在确定与新生儿iGBS疾病相关的炎症、细胞凋亡和持久CNS后遗症的主要驱动因素（项目D）。特别是，我们将exlpore中性粒细胞和中性粒细胞胞外陷阱在GBS诱导的血行性脑膜炎和潜在的神经元损伤的发病机制中的作用。该工作方案的重点是非洲年轻的早期职业受训者的教育发展/进步，包括儿科医生，研究技术人员，博士和博士后候选人，同时也与莫桑比克和南非以外的其他非洲地点和合作伙伴联系。职业发展计划是集中组织的，以确保高标准的培训，以获得更多的了解iGBS疾病和战略的实施，以减轻不仅iGBS疾病的负担，而且其他原因和新生儿败血症和脑膜炎在非洲。

An important cause of neonatal sepsis in developed and developing countries is Streptococcus agalactiae or Group B Streptococcus (GBS), a Gram-positive β-haemolytic, encapsulated diplococci. Pregnancy related GBS colonisation may lead to infant invasive GBS disease (iGBS), including meningitis or sepsis, with high mortality risk. There were an estimated 319,000 invasive GBS disease cases in infants under 3 months of age in 2015, 90,000 of which were fatal and a further 10,000 of whom developed moderate to severe neurological disabilities primarily secondary to GBS meningitis. In addition, recent studies highlight that adverse NDI outcomes are also extending to survivors of iGBS sepsis. Of the estimated mortality and morbidity associated with GBS disease in neonates, more than half were in Africa. To reduce the incidence of neonatal GBS disease, it is important to understand the long-term consequences of the disease. There is a dearth of information on the long-term outcomes of neonatal GBS infection, such as neurodevelopmental impairment. Combined with long-term morbidity and mortality outcomes, these data are particularly important to assess the burden of disease in more detail and to evaluate the economic burden. Thus, the aim of project A is to further investigate the risk of neurodevelopmental impairment (NDI) and socioemotional behaviours in children who survived neonatal or infant invasive (iGBS) disease in South Africa and Mozambique. For project B we will also measure long-term health related quality of life and economic costs that arise as a consequence of iGBS disease. The acute inflammatory response caused by GBS and the bacteria itself, most likely leads to neurological disabilities. Thus, to complement the human based studies assessing the NDI in iGBS survivors we aim to undertake a study characterizing the immune response in iGBS survivors (project C). In line with human studies investigating the immune response to iGBS disease in neonates, we aim to also undertake a series of in vitro and in vivo animal studies aimed at determining the primary drivers of inflammation, apoptosis and the long-lasting CNS sequelae associated with neonatal iGBS disease (project D). In particular we will exlpore the role of neutrophils and neutrophil extracellular traps in the pathogenesis of GBS-induced haematogenous meningitis and potential neuronal damage. The work program is focused on educational development / advancement for young early-career trainees in Africa, ranging from paediatricians, research technicians to doctoral and postdoctoral candidates within the consortium also reaching out to other African sites and partners outside of Mozambique and South Africa. The career developmental plan is centrally organized, to ensure high standards of training to gain more insights into iGBS disease and the implementation of strategies to alleviate the burden of not only iGBS disease, but also other causes and neonatal sepsis and meningitis in Africa.