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 the events resulting in endothelial hyperpermeability and vascular leakage, a hallmark of severe dengue disease. However, the role for this increase in NEU1-4 activity in the viral lifecycle was not understood. In an siRNA screen of enzymes involved in the sphingolipid metabolic pathway, we uncovered that NEU1-4 are vital for DENV2 infectious virus release. Thus, we uncovered that NEU1-4 activity was not only a component of dengue pathogenesis, but was also vital to the lifecycle of DENVs. To understand why NEU1-4 functionality is required for infectious virus release, we have systematically investigated how specific steps of the viral lifecycle is affected by loss of function of NEU1-4. Additionally, we have completed time course analyses utilizing qRT-PCR and immunofluorescence assays to examine how NEU1-4 mRNA and protein activity are modulated during infection. Here we will present our data that sheds light on the roles of NEU1-4 during the DENV2 lifecycle.

Inhibition of human sialidases disrupts dengue virus replication.

ACS Spring Meeting 2021

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