Molecular Insight into Dengue Virus Pathogenesis and Its Implications for Disease Control

Abstract

Dengue virus (DENV) is a mosquito-transmitted RNA virus that infects an estimated 390 million humans each year. Here, we review recent advances in our understanding of the biology of DENV and describe knowledge gaps that have impacted the development of effective vaccines and therapeutics.

Figure 1. Cell biology of DENV infection

DENV interacts with target cells via one or more host factors that enhance attachment. DENV subsequently is internalized by endocytosis and fuses with membranes of the late endosome in a pH-dependent manner. Virus binding and membrane fusion is orchestrated by the envelope (E) protein, which is composed of three domains (top center, DI, shown in red; DII, shown in yellow; and DIII, shown in blue). Viral RNA translation and replication occurs in association with membranes of the endoplasmic reticulum (ER). Newly synthesized viral RNA is packaged into immature virions, which bud into the ER lumen. During egress, the virion undergoes a maturation step defined by cleavage of the prM protein by furin proteases (orange spheres). DENV infection is detected by host pattern recognition receptors that selectively bind viral RNA molecules including TLRs and RIG-I-like receptors (RLRs). Additionally, DENV infection activates the DNA sensor cGAS and STING pathway via unknown mechanisms. These cell-intrinsic host defense systems stimulate the production of IFNs to promote expression of antiviral ISGs. DENV has evolved mechanisms to antagonize antiviral pathways including the NS2B/3-mediated cleavage of STING and NS5-mediated degradation of STAT2. (Inset) An increasingly detailed understanding of the structural basis of antibody recognition has emerged. Antibodies have been characterized that bind epitopes (in green) on the virion comprised of a single or multiple E proteins. For example, the DIII lateral ridge epitope is contained within a single E protein (top), whereas the E-dimer-dependent quaternary epitope is composed of residues of both E proteins in the anti-parallel dimer (bottom). In contrast, other mAbs bind epitopes not predicted to be accessible using existing models of virion structure (middle).