Human sialidase activity is vital for dengue virus serotype 2 infection

The human sialidase enzymes (or neuraminidases, NEU1-4) are glycoside hydrolases that catalyze the removal of sialic acid residues from glycoconjugates, including many bioactive glycoproteins and glycolipids. Through their physiochemical effect on glycoconjugates, sialic acid residues are thought to play vital roles in the control of cellular signaling. In previous studies, it was demonstrated that NEU1-4 activity was increased in cells infected with dengue virus serotype 2 (DENV2). Additionally, it was demonstrated that the DENV2 NS1 protein was sufficient for inducing increased NEU1-4 activity in both in vivo and in vitro models, and that this increased activity was linked to endothelial hyperpermeability and vascular leakage, a hallmark of severe dengue disease. However, the role of increased NEU1-4 activity in the viral lifecycle was not understood. Here, we used siRNA-mediated loss of function studies to evaluate the effect of inhibition of sialidase activity on the DENV2 lifecycle. Our analyses uncovered that apart from their importance for viral pathogenesis, NEU1-4 activity was vital for DENV2 viral replication and egress. Moreover, we characterized the inter-relationship between NEU 1-4, and determined that there was a transcriptional dependency of NEU1-3 on NEU4.