Metabolic engineering of sialic acids to visualize host-pathogen interactions and inhibit bacterial and viral infections.
Sialic acids play a major role in host-pathogen interactions. For example, the influenza virus infection cycle depends on the binding and eventual hydrolysis of host-cell-surface sialic acids by haemagglutinin and neuraminidase. Some pathogens, such as non-typeable Haemophilus influenzae (NTHi) evade the immune system by presenting host-derived sialic acids. This inspired us to develop tools to visualize and inhibit these interactions to find novel therapeutics to combat bacterial and viral infections.
Recently, we reported sialic acid-based probes to visualize the transfer of host sialic acids to NTHi. We did this in an in vitro model of the human respiratory tract by modifying the bronchial epithelial cell sialic acids by adding either azidoacetyl (Az)-, or propargyloxycarbonyl (Poc)- modified sialic acids. We then could visualize the decoration of NTHi with the Az-sialic acid and we demonstrated efficient inhibition of sialic acid transfer with bio-orthogonal chemistry, abrogating serum resitance of NTHi. Poc-sialic acid, although similar to Az in length and flexibility, was not transferred to NTHi. We have shown that Poc-modified sialic acids are largely resistant to cleavage by viral neuraminidases. We developed a small library of linkers for both azide and alkyne sialic acid derivatives and studied the reason why this difference is observed and the mechanism through which the binding takes place, as well as synthesized analogues that would yield the opposite effect.