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组链球菌，一种革兰氏阳性β溶血性包膜双球菌。与妊娠相关的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疾病病例，其中90,000例是致命的，另有10,000例发展为主要继发于GBS脑膜炎的中到重度神经残疾。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。在新生儿中与GBS疾病相关的估计死亡率和发病率中，超过一半在非洲。为了减少新生儿GBS疾病的发病率，了解这种疾病的长期后果是很重要的。关于新生儿GBS感染的长期结果，如神经发育障碍，缺乏信息。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尤为重要。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(IGBS)疾病幸存者的神经发育障碍(NDI)和社会情绪行为的风险。对于B项目，我们还将衡量由于IGBS疾病而产生的与健康相关的长期生活质量和经济成本。GBS和细菌本身引起的急性炎症反应很可能导致神经残疾。因此，为了补充评估IGBS幸存者的NDI的基于人类的研究，我们的目标是开展一项表征IGBS幸存者的免疫反应的研究(项目C)。与研究新生儿IGBS疾病免疫反应的人类研究一致，我们的目标也是进行一系列体外和体内动物研究，旨在确定炎症、细胞凋亡和与新生儿IGBS疾病相关的长期中枢神经系统后遗症的主要驱动因素(项目D)。特别是，我们将阐述中性粒细胞和中性粒细胞胞外陷阱在GBS诱导的血源性脑膜炎和潜在的神经元损伤发病机制中的作用。该工作计划的重点是为非洲年轻的职业生涯早期实习生提供教育发展/晋升，范围从儿科医生、研究技术员到该联盟内的博士和博士后候选人，并与莫桑比克和南非以外的非洲其他地点和合作伙伴进行接触。职业发展计划是集中组织的，以确保高标准的培训，以更深入地了解IGBS疾病，并实施战略，不仅减轻IGBS疾病的负担，而且减轻其他原因以及非洲新生儿败血症和脑膜炎的负担。

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.