Developing novel therapeutic strategies to target stroke-associated infection

超急性卒中护理的改善和机械取栓去除血栓的引入意味着越来越多的缺血性卒中患者在其原发性神经损伤后存活下来。然而，他们的康复往往受到身体残疾和认知障碍的影响[1,2]。目前仅在英国就有130万中风幸存者，其社会经济成本估计为每年260亿英镑[3,4]。感染，尤其是细菌性肺炎，是卒中的常见并发症，尽管有抗生素治疗和现代卒中单位护理，但感染会增加死亡率，并与幸存者较差的功能预后相关[5-8]。感染对中风恢复的广泛影响使其在中风优先事项确定伙伴关系bbb10最近的报告中被列为中风研究的十大优先事项之一。在随机试验中，预防性抗生素并没有降低感染发生率或改善临床结果[10,11]。因此，改善脑卒中相关感染（SAI）的临床结果是一个尚未满足的主要需求。我们已经证明边缘区（MZ） B细胞功能障碍，IgM抗体降低在卒中后感染易感性中起主要作用，使用静脉注射免疫球蛋白（IVIg）治疗（IgM-IVIg）可以改善菌血症和炎症。然而，这需要进一步优化，例如了解延迟治疗时间以及与当前标准护理治疗（如抗生素）的相互作用。此外，IgM-IVIg是一种有限的资源，需要持续的人类献血来生产。在这项研究中，我们将在使用IgM-IVIg取得初步成功的基础上，研究生产治疗性抗体的替代方法，测试它们的功效，并与辅助抗生素治疗相结合，以增强它们的抗菌和免疫调节特性。

Improvements in hyperacute stroke care and the introduction of mechanical thrombectomy for clot removal mean increasing numbers of ischemic stroke patients are surviving their primary neurological injury. However their recovery is often compromised by physical disability and cognitive impairment [1, 2]. There are currently 1.3 million stroke survivors in the UK alone carrying a socioeconomic cost estimated at £26 billion per year [3, 4]. Infection, in particular bacterial pneumonia, is a common complication of stroke, which increases mortality and is associated with poorer functional outcome in survivors, despite antibiotic therapy and modern stroke unit care [5-8]. The extensive impact of infection on stroke recovery has led to it being listed in the top 10 priorities for stroke research in a recent report from the Stroke Priority Setting Partnership [9]. Prophylactic antibiotics did not reduce infection incidence or improve clinical outcome in randomised trials [10, 11]. Improving clinical outcomes from stroke-associated infection (SAI) is therefore a major unmet need.We have shown marginal zone (MZ) B cell dysfunction, and reduced IgM antibody plays a major role in post-stroke infection susceptibility and administration of IgM using intravenous immunoglobulin (IVIg) therapy (IgM-IVIg) can improve bacteraemia and inflammation. However, this requires further optimisation such as understanding delayed treatment times and interactions with current standard of care treatments such as antibiotics. Furthermore, IgM-IVIg is a limited resource requiring continuous human blood donation for its production. In this study, we will build on our initial success using IgM-IVIg and investigate alternative methods to produce therapeutic antibodies, test them for efficacy and combine with adjunct antibiotic treatment to enhance their anti-bacterial and immunomodulatory properties.