Antibodies against the Envelope Glycoprotein Promote Infectivity of Immature Dengue Virus Serotype 2

Júlia Da Silva-Voorham, Izabela A. Rodenhuis-Zybert, Vanesa Ayala Nunez, Tonya M. Colpitts, Heidi van der Ende-Metselaar, Erol Fikrig, Michael S. Diamond, Jan Wilschut, Jolanda M. Smit

OnderzoeksoutputAcademicpeer review

35 Citaten (Scopus)
161 Downloads (Pure)

Samenvatting

Cross-reactive dengue virus (DENV) antibodies directed against the envelope (E) and precursor membrane (prM) proteins are believed to contribute to the development of severe dengue disease by facilitating antibody-dependent enhancement of infection. We and others recently demonstrated that anti-prM antibodies render essentially non-infectious immature DENV infectious in Fc gamma-receptor-expressing cells. Immature DENV particles are abundantly present in standard (st) virus preparations due to inefficient processing of prM to M during virus maturation. Structural analysis has revealed that the E protein is exposed in immature particles and this prompted us to investigate whether antibodies to E render immature particles infectious. To this end, we analyzed the enhancing properties of 27 anti-E antibodies directed against distinct structural domains. Of these, 23 bound to immature particles, and 15 enhanced infectivity of immature DENV in a furin-dependent manner. The significance of these findings was subsequently tested in vivo using the well-established West Nile virus (WNV) mouse model. Remarkably, mice injected with immature WNV opsonized with anti-E mAbs or immune serum produced a lethal infection in a dose-dependent manner, whereas in the absence of antibody immature WNV virions caused no morbidity or mortality. Furthermore, enhancement infection studies with standard (st) DENV preparations opsonized with anti-E mAbs in the presence or absence of furin inhibitor revealed that prM-containing particles present within st virus preparations contribute to antibody-dependent enhancement of infection. Taken together, our results support the notion that antibodies against the structural proteins prM and E both can promote pathogenesis by enhancing infectivity of prM-containing immature and partially mature flavivirus particles.

Originele taal-2English
Artikelnummere29957
Aantal pagina's10
TijdschriftPLoS ONE
Volume7
Nummer van het tijdschrift3
DOI's
StatusPublished - 14-mrt-2012

Citeer dit