Intrinsic ADE: The Dark Side of Antibody Dependent Enhancement During Dengue Infection

Abstract

Dengue fever is an Aedes mosquito-borne illness caused by any one of the four different dengue virus (DENV) serotypes (1-4) and manifests in the form of symptoms ranging from mild or asymptomatic to severe disease with vascular leakage, leading to shock, and viral hemorrhagic syndrome. Increased risk of severe disease occurs during secondary infection with a virus serotype distinct from that of prior dengue infection. This occurs by antibody dependent enhancement (ADE) of infection, wherein sub-neutralizing antibodies against the virus particles opsonize dengue virus entry via formation of immune complexes that interact with fragment crystallizable gamma receptors (FcγR) on monocytes, dendritic cells, and macrophages. The ADE phenomenon has two components: Extrinsic and Intrinsic ADE. While extrinsic ADE contributes to enhanced virus entry, intrinsic ADE results in heightened virus production by inhibition of type1 interferon and activation of interleukin-10 biosynthesis, thereby favoring a Th2 type immune response. Intrinsic ADE has greater contribution in enhancing Dengue replication as compared to extrinsic ADE. Detailed elucidation of intrinsic ADE during secondary dengue infection can increase our understanding of DENV-pathogenesis and aid in the development of host-targeting antivirals. Here we review literature focusing on intrinsic factors contributing to severe dengue pathology and suggest possible avenues for further research.

Keywords: antibody dependent enhancement (ADE); dengue; extrinsic ADE; intrinsic ADE; pathogenesis.

Figure 1

Innate immune response during ADE and non-ADE dengue infection. Canonical non-ADE mediated entry occurs via receptor-mediated endocytosis. Upon entry, the DENV particles are internalized in endosomes and are recognized by the pathogen recognition receptors TLR-3 and 7. Release of viral RNA from endosomes is recognized by RIGI and MDA5 which triggers production of pro-inflammatory cytokines IFN-γ and IL-8. This activates the JAK/STAT pathway resulting in expression of IFN-γ, IL-12, and Nitric Oxide radicals. Virus entry via FcγR-antibody in dengue-ADE caused expression of TANK and SARM which inhibits TLR signaling. Production of anti-inflammatory cytokines IL-10 and IL-6 ensues and expression of SOCS3 as a result inhibits JAK/STAT pathway. This results in inhibition of pro-inflammatory cytokine production and causing a TH-2 biased immune response and increased “burst” size.