Developing novel therapeutic strategies to target stroke-associated infection

超急性卒中治疗的改进和用于血栓清除的机械取栓术的引入意味着越来越多的缺血性卒中患者正在从他们的初级神经损伤中存活下来。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，仅英国就有130万中风幸存者，估计每年的社会经济成本为260亿英镑[3，4]。感染，特别是细菌性肺炎，是中风的常见并发症，它增加了死亡率，并与幸存者较差的功能结局有关，尽管接受了抗生素治疗和现代中风病房护理[5-8]。感染对中风康复的广泛影响使其在中风优先设置伙伴关系最近的一份报告中被列为中风研究的十大优先事项[9]。在随机试验中，预防性抗生素不能降低感染发生率或改善临床结果[10，11]。因此，改善卒中相关感染(SAI)的临床结果是一个主要的未得到满足的需求。我们已经发现边缘带(MZ)B细胞功能障碍，而IgM抗体降低在卒中后感染的易感性中起主要作用，使用静脉免疫球蛋白(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，例如了解延迟的治疗时间以及与目前标准的护理治疗(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才能生产。在这项研究中，我们将在使用IgM-IVIg的初步成功的基础上，研究生产治疗性抗体的替代方法，测试它们的有效性，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.