Developing novel therapeutic strategies to target stroke-associated infection

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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.