Exploiting the molecular mimicry of Non-typeable Haemophilus influenzae with ketodeoxynonulosonic acid: Confusing the bacterium in its own game

Abstract

Abstract The distinctly human mucosal commensal and opportunistic pathogen non-typeable Haemophilus influenzae (NTHi) is frequently responsible for acute exacerbations of chronic obstructive pulmonary disease (COPD) in adults, and causes otitis media in infants. A key tool in this organism’s pathogenic arsenal is its ability to mimic glycans on human cells, which like all vertebrate cells, display diverse glycans with terminal 9-carbon-backbone monosaccharides called sialic acids. NTHi pathogenesis is related to its remarkably efficient uptake of trace amounts of free host N-acetylneuraminic acid (Neu5Ac, the primary sialic acid in humans) allowing “cloaking” of surface glycans of lipooligosaccharides (LOS) with this monosaccharide. This helps evasion from host immune clearance by “self-mimicry”, while facilitating colonization and biofilm formation. Since the mechanism of NTHi sialic acid uptake evolved by convergent evolution and is not selective for Neu5Ac, we propose to exploit this mimicry using another sialic acid called 2-keto-3-deoxy-D-glycero-D-galacto-nononic acid (Kdn). While NTHi growth was unaffected by Kdn in media, we found glycosidically-bound Kdn in LOS, which made NTHi sensitive to human sera and whole blood killing. The role of sialylation in vivo was further explored using a novel mouse model, with a human-like sialic acid profile. This mouse showed better acute NTHi colonization of the respiratory tract following intranasal challenge compared to wild type mice. Since Kdn is a metabolic byproduct in humans and should be non-toxic, the possibility of using Kdn as a safe intervention against NTHi colonization and subsequent infection is currently being explored using this mouse model.