Abstract
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 Fcγ-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.
Highlights
Dengue virus (DENV) is the leading cause of mosquito-borne viral disease in the world
We selected 25 mAbs including 13 that mapped to domain III (DIII), 11 that localized to E Domain I (DI)/domain II (DII), and 1 that bound E but could not be mapped by yeast surface display of E proteins
In agreement with previous data with anti-precursor membrane (prM) antibodies [26], we found that enzymatic activity of furin in the target cell was required for facilitating infectivity of anti-E antibody-opsonized immature particles
Summary
Dengue virus (DENV) is the leading cause of mosquito-borne viral disease in the world. It is estimated that over 50 million DENV infections occur annually, resulting in 500,000 hospitalizations and over 20,000 deaths [1]. The four antigenically distinct serotypes (DENV 1, 2, 3 and 4) are transmitted to humans by bites of female Aedes aegypti and Aedes albopictus [1,2]. Most infections are asymptomatic, DENV infection may result in a wide spectrum of clinical symptoms, ranging from a febrile illness (dengue fever [DF]) to a life-threatening hemorrhagic and capillary leak syndrome (dengue hemorrhagic fever [DHF]/ dengue shock syndrome [DSS]) [1,2]. Individuals experiencing a later secondary infection with a distinct DENV serotype are at greater risk for developing severe disease
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