Engineering of a Fusion Protein Therapeutic to Combat E. Coli K1 Meningitis

Overview

Acute bacterial meningitis is a medical crisis with a poor prognosis, especially if treatment is prolonged. Development of bacteremia and sepsis is common during infection and neurological sequelae is prevalent in survivors. Escherichia coli K1 infection is a major cause of neonatal meningitis. Although mortality has decreased since the advent of antibiotics, morbidity has remained relatively static due to the inadvisable use of anti-inflammatory corticosteroid treatment in neonates. The increased incidence of antibiotic resistance as well as the limitations of adjunctive anti-inflammatory therapies are hurdles in effective treatment, necessitating the development of novel therapeutics. In this study, the concomitant use of endoE and IL-10 in the form of a post-translational fusion protein was investigated as such a therapeutic modality. Results from an enzyme activity assay indicate that an endoE/IL-10 conjugate retained the kinetic activity of wild-type endoE in selectively hydrolyzing α-2,8-linked sialic acid. This capsule-depolymerizing activity was also realized in a complement sensitivity assay, which demonstrated the ability of the conjugate to expose complement-resistant bacteria to killing by human blood serum (a source of complement). Furthermore, the conjugate significantly reduced TNF- α production in murine macrophages induced to produce proinflammatory cytokines by heat-killed E. coli K1. These findings demonstrate the potential of the endoE/IL-10 conjugate as a therapeutic for treating E. coli K1 meningitis, as it both attenuates E. coli K1 virulence by selectively degrading its pathogenic capsule and reduces associated inflammation.

Competition history

• AJAS 2019 Category not listed

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