Dengue Virus Figures

Guzman, M. G. et al. Dengue: A continuing global threat. Nature Reviews Microbiology 8, S7–S16 (2010). doi:10.1038/nrmicro2460

The dengue virus has a roughly spherical shape. Inside the virus is the nucleocapsid, which is made of the viral genome and C proteins. The nucleocapsid is surrounded by a membrane called the viral envelope, a lipid bilayer that is taken from the host. Embedded in the viral envelope are E and M proteins that span through the lipid bilayer. These proteins form a protective outer layer that controls the entry of the virus into human cells. © 2011 Nature Education

Top) Dengie Virus Structure pre-infection Bottom) Dengue Virus inside the endosome. Hydrophobic amino acids which fuse with endosome mebrane shown in red

The dengue virus attaches to the surface of a host cell and enters the cell by a process called endocytosis. Once deep inside the cell, the virus fuses with the endosomal membrane and is released into the cytoplasm. The virus particle comes apart, releasing the viral genome. The viral RNA (vRNA) is translated into a single polypeptide that is cut into ten proteins, and the viral genome is replicated. Virus assembly occurs on the surface of the endoplasmic reticulum (ER) when the structural proteins and newly synthesized RNA bud out from the ER. The immature viral particles are transported through the trans-Golgi network (TGN), where they mature and convert to their infectious form. The mature viruses are then released from the cell and can go on to infect other cells. © 2005 Nature Publishing Group Mukhopadhyay, S., Kuhn, R. J., & Rossmann M. G. A structural perspective of the flavivirus life cycle. Nature Reviews Microbiology 3, 13–22 (2005). doi:10.1038/nrmicro1067

a | The dengue virus life cycle and sources of antigens are shown. Dengue virions bind to cell surface receptors (these have not been completely characterized), and the virions are internalized through endocytosis. Acidification of the endocytic vescicle leads to rearrangement of the surface envelope (E) glycoprotein, fusion of the viral and vesicle membranes and release of viral RNA into the cytoplasm. Viral genomic RNA is then translated to produce viral proteins in endoplasmic reticulum (ER)-derived membrane structures, and the viral proteins and newly synthesized viral RNA assemble into immature virions within the ER lumen. Cleavage of the viral precursor membrane (pre-M) protein by the host cell enzyme furin leads to the formation of mature virions, which are secreted from the cell. In addition, some of the synthesized non-structural protein 1 (NS1) is expressed on the plasma membrane of the cell or secreted, and some virions are secreted in an immature form. Mature and immature virions induce antibody responses to the E protein, and these antibodies can function in neutralization or in antibody-dependent enhancement of infection. Immature virions also induce antibody responses to the pre-M protein. Antibodies specific for NS1 can interact with membrane-bound NS1 and cause complement-dependent lysis of virus-infected cells. b | The structure of the dengue virus E glycoprotein ectodomain and characteristics of E protein-specific antibodies are shown. The three domains of the E protein are coloured in red (domain I), yellow (domain II) and blue (domain III). c | The mechanisms of neutralization and enhancement by dengue virus-specific antibodies are shown. At high levels of epitope occupancy, antibodies can block the binding of virions to the cellular receptor or can block fusion at a post-binding stage. At lower epitope occupancy levels, antibodies can enhance the uptake of virions into cells by interacting with immunoglobulin (Fc) receptors.

a | The dengue virus life cycle and sources of antigens are shown. Viral attachment, internalization, fusion and translation proceed as described in Fig. 1. Newly synthesized viral proteins enter the MHC class I and II presentation pathways and viral peptide epitopes are presented on the cell surface within the binding groove of MHC molecules. MHC class II molecules present peptides to CD4+ T cells, which principally produce cytokines but are also capable of lysing infected cells. MHC class I molecules present peptides to CD8+ T cells, which principally lyse infected cells but also produce cytokines. b | A schematic of the dengue virus polyprotein is shown at the top and the locations of well-defined epitopes that are recognized by human T cells are marked by arrows. c | Three of the well-defined T cell epitopes are shown to demonstrate the incomplete sequence conservation of typical T cell epitopes. The location of the epitope, its recognition by CD4+ or CD8+ T cells and its HLA restriction are indicated at the top. The predominant sequences for each of the four serotypes are shown. Residues that are completely conserved are shown in black and residues that are not completely conserved are shown in red. d | Variant epitopes alter the T cell functional response, and the figure shows two examples. The full agonist peptide (top) induces a full range of T cell responses — production of multiple cytokines (for example, IFNγ, TNF and CCL4) and lysis of the infected cell. A partial agonist peptide varying at one residue (bottom; altered residue in red) induces a skewed functional response, involving production of some cytokines (CCL4 in this example) but little production of other cytokines (such as IFNγ) and inefficient cell lysis. C, capsid protein; CCL4, CC-chemokine ligand 4; E, envelope protein; ER, endoplasmic reticulum; IFNγ, interferon-γ; NS, non-structural protein; pre-M, precursor membrane protein; TNF, tumour necrosis factor

Similarity of the NS1 wing α/β subdomain to the RIG-I family of innate immune proteins. An SF2 helicase domain of RIG-I [blue; PDB accession code 3TBK (25)] is superimposed on the WNV NS1 wing domain (yellow). Orange, connector subdomain.

Virus inoculation by Aedes aegypti mosquitoes results in viral dissemination, which in turn results in disease manifestations; high virus titres are necessary but not sufficient to cause severe disease. Viral and host factors affect early viral replication and influence the level of viraemia. Other host factors affect the levels of production of various cytokines (such as interferon-γ (IFNγ) and tumour necrosis factor (TNF)) and determine the severity of illness for any given level of viraemia. APL, altered peptide ligand.