Abstract
Emerging infections of mosquito-borne Zika virus (ZIKV) pose an increasing threat to human health, as documented over the recent years in South Pacific islands and the Americas in recent years. To better understand molecular mechanisms underlying the increase in human cases with severe pathologies, we recently demonstrated the functional roles of structural proteins capsid (C), pre-membrane (prM), and envelop (E) of ZIKV epidemic strains with the initiation of viral infection in human cells. Specifically, we found that the C-prM region contributes to permissiveness of human host cells to ZIKV infection and ZIKV-induced cytopathic effects, whereas the E protein is associated with viral attachment and early infection. In the present study, we further characterize ZIKV E proteins by investigating the roles of residues isoleucine 152 (Ile152), threonine 156 (Thr156), and histidine 158 (His158) (i.e., the E-152/156/158 residues), which surround a unique N-glycosylation site (E-154), in permissiveness of human host cells to epidemic ZIKV infection. For comparison purpose, we generated mutant molecular clones of epidemic BeH819015 (BR15) and historical MR766-NIID (MR766) strains that carry each other’s E-152/156/158 residues, respectively. We observed that the BR15 mutant containing the E-152/156/158 residues from MR766 was less infectious in A549-Dual™ cells than parental virus. In contrast, the MR766 mutant containing E-152/156/158 residues from BR15 displayed increased infectivity. The observed differences in infectivity were, however, not correlated with changes in viral binding onto host-cells or cellular responses to viral infection. Instead, the E-152/156/158 residues from BR15 were associated with an increased efficiency of viral membrane fusion inside infected cells due to conformational changes of E protein that enhance exposure of the fusion loop. Our data highlight an important contribution of E-152/156/158 residues to the early steps of ZIKV infection in human cells.
Highlights
Mosquito-borne Zika (ZIKV), dengue (DENV), Yellow fever (YFV) and Japanese encephalitis (JEV) viruses belonging to flavivirus genus (Flaviviridae family), are four enveloped RNA viruses of significant public health concern worldwide [1,2,3,4]
Most flavivirus E proteins are post-translationally modified by addition of a single N-linked oligosaccharide on residue N-154 located within the EDI-loop [16]
Our goal was to determine whether three E residues—isoleucine 152 (Ile152), threonine 156 (Thr156), and histidine 158 (His158)—which surround the Asn154 composing the N-glycosylation site NDT, may have any effect on Zika virus (ZIKV)’s ability to infect human cells
Summary
Mosquito-borne Zika (ZIKV), dengue (DENV), Yellow fever (YFV) and Japanese encephalitis (JEV) viruses belonging to flavivirus genus (Flaviviridae family), are four enveloped RNA viruses of significant public health concern worldwide [1,2,3,4]. Recent ZIKV global outbreaks, with Brazil at the epicentre, highlighted how a previously neglected flavivirus can turn into a severe threat for human health. Flaviviruses contain a genomic single-stranded positive RNA encoding a single large polyprotein that is subsequently cleaved by cellular and viral proteases into three structural proteins (C, prM/M and E) and seven nonstructural proteins (NS1 to NS5). The latter are responsible for virus replication, assembly and escape from host immune system, while structural proteins form the viral particle surrounding genomic viral RNA. Fusion of viral and cellular membranes occurs after E protein conformational changes triggered by low pH [14]. Flavivirus E proteins represent a major target for neutralizing antibodies but, at the same time, can be involved in enhancement/cross-reactivity of reactive antibodies [18,19,20,21]
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