Dissecting the Cell Entry Pathway of Dengue Virus

Dengue virus Dengue virus (DENV) is the most common arthropod-borne infection worldwide with 50–100 million cases annually. Despite its high clinical impact, little is known about the infectious cell entry pathway of the virus. Previous studies have shown conflicting evidence about whether the virus fuses directly with the cell plasma membrane or enters cells by receptor-mediated endocytosis.

Entry of DENV into hosts cells is mediated by the virus envelope glycoprotein E, which is organized in 90 homodimers on the surface of the virion. The E glycoprotein is involved in interaction with cellular receptors as well as the subsequent membrane fusion process. In vitro studies show that membrane fusion is triggered on exposure of the virus to low pH, when the E proteins undergo a dramatic re-organization which leads to the formation of trimers. The crystal structure of the E protein has been solved in its dimeric pre-fusion, and trimeric post-fusion configurations. Although much is known about the molecular mechanisms involved in the membrane fusion process, many critical questions regarding the cell entry pathway of flaviviruses remain unanswered.

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A recent paper dissects the cell entry pathway of DENV by tracking single fluorescently-labeled DENV particles in living cells expressing various fluorescent cellular markers, using real-time multi-color fluorescence microscopy (Dissecting the Cell Entry Pathway of Dengue Virus by Single-Particle Tracking in Living Cells. 2008 PLoS Pathog 4(12): e1000244). It shows that DENV particles are delivered to pre-existing clathrin-coated pits by diffusion along the cell surface. Following clathrin-mediated uptake, the majority of DENV particles are transported to early endosomes, which mature into late endosomes, where membrane fusion occurs. This is the first study that describes the cell entry process of DENV at the single particle level and therefore provides unique mechanistic and kinetic insights into the route of entry, endocytic trafficking behavior, and membrane fusion properties of individual DENV particles in living cells.

This work opens new avenues in flavivirus biology and will lead toward a better understanding of the critical determinants in DENV infection. Single-particle tracking has substantially enriched our knowledge of virus cell entry mechanisms and has revealed previously unknown aspects of virus-host interactions. The mechanistic and kinetic insights offered by this technique provide a better understanding of disease pathogenesis and may lead to a rational design of antiviral drugs and vaccines.

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