Developing novel mannose-binding lectin therapies to prevent, diagnose and treat infections in children

This thesis concerns the extensive properties of the immune molecule mannose-binding lectin (MBL). The work centres around the broad-range sugar recognition properties of MBL for microbes, with an emphasis on bacterial, yeast and viral infections. This thesis focuses on translational research in particular on the integration of MBL into the clinic to provide more effective diagnostic tools and therapies for childhood diseases. In Part I of this thesis, we utilise the properties of MBL to bind, concentrate and rapidly diagnose infections using mass spectrometry. We found that MBL molecules conjugated to magnetic beads are effective at binding a wide range of different pathogens within blood samples. We further found that the beads are able to enrich the samples by significantly increasing concentrations and reducing host background. We compared this approach with the rapid diagnosis method currently in use at GOSH’s clinical microbiology. We observe that the MBL-based method is more successful at identifying yeast infections than the current standard and is equally as effective at detecting bacterial infections. Part II addresses the potential of MBL therapy to prevent and treat chronic infections, particularly biofilms. Biofilms are associated with increased mortality and morbidity rates, as well as an increased risk of antimicrobial resistance development. We show that MBL is able to bind bacteria and reduce the formation of these biofilms, and also enhances the immune response to established biofilm infections. The final chapter of this thesis focuses on the role of MBL in protection against the novel severe-acute respiratory syndrome coronavirus 2 (SARS-CoV-2). In particular we show that MBL deficiency or low MBL serum levels may be a risk factor in the development of paediatric multisystem inflammatory syndrome temporally associated with SARS-CoV-2 (PIMS-TS), an inflammatory syndrome appearing in response to SARS-CoV-2 infection observed in children. We observed significant reductions in SARS-CoV-2 binding to lung epithelium when using MBL mixtures previously prepared and tested in the clinic