Source: UMASS Medical School Center for Translational Research in Immunology and Biodefense
This visualization adapted from the University of Massachusetts Medical School represents the process by which a dengue virus releases its genetic contents inside a host cell, allowing viral replication. The key players are proteins found on the viral surface called envelope proteins, which change their structure when the virus is endocytosed, or taken inside the cell. This structural change enables the viral membrane to fuse with the endosomal membrane, and the virus' RNA to enter the cytoplasm of a host cell. There, ribosomes will make viral proteins that will spread to other cells through the replication and secretion of new viral particles.
The reproductive goal of all viruses is to deposit their genetic material inside a host cell and hijack its protein production. However, each virus type differs in makeup, protein structure, and the methods it employs to take cells over. For dengue virus and other mosquito-borne viruses, infection starts in skin and immune cells local to the mosquito bite. Like most RNA viruses, dengue virus replicates in the cytoplasm of a host cell. It does this by exploiting ribosomes, which synthesize the proteins that ultimately assemble new virus particles inside the endoplasmic reticulum. When this happens, infection may spread to other types of cells and tissues, including the bloodstream.
Dengue is an enveloped virus, which means it's surrounded by a protein layer and a lipid bilayer. Inside this viral envelope is a protein coat called a capsid, and the RNA genome. To infect a host cell, the dengue virus must find a way to penetrate the cell's plasma membrane. Once inside, it must find a way to fuse yet another cellular membrane—the host cell's endosomal membrane—with its own so that the virus' RNA cargo can be released.
Endocytosis is the process by which cells let in certain molecules, including hormones and neurotransmitters, from the outside. The dengue virus gains access to the cell at non-specific receptors, which recognize sugar molecules attached to the envelope proteins. An adaptor protein inside the cytoplasm also participates in the process, as do lattices of clathrin—the purple structure visible at the beginning of the animation—located at the inside of the cell membrane. The membrane and receptor invaginate, or fold in, to form a clathrin-coated vesicle, or membrane-bound sac. Once inside the cell, the free-moving vesicle quickly loses its coat. (The purple fragments in the animation represent pieces of this broken coat.)
ATP inside the cell activates a proton pump at the endosome membrane, flooding the inside of the endosome with protons. In an uninfected cell, this routine mechanism acidifies the environment, removing extracellular materials trapped inside endosomes and freeing receptors to return to the cell surface and repeat their function. However, in an infected cell, acidification causes the envelope proteins on the virus to undergo a critical structural transformation. When pH drops inside the endosome, the envelope proteins convert from dimer compounds, which are made of two identical proteins, into trimer compounds, which are made of three. The trimers move freely in the surface of the viral membrane, and one end of each trimer stands upright. Exposed to the aqueous environment, the trimers' extremely hydrophobic tips seek out the surrounding endosome's lipid membrane. The tips stab into this membrane and, through shape-shifting movements, the trimers ultimately fuse the endosomal and viral membranes. The fusion pore that forms permits the viral contents to empty into the cell's cytoplasm.
Because proteins are so small and cannot be visualized by microscopes, scientists have developed images created by X-ray crystallography, a method used to produce a three-dimensional picture of the density of electrons within a crystal. From such a picture, atomic positions, chemical bonds, and other information can be derived. The positions of the atomic nuclei are deduced from these data, and a three-dimensional image can be generated.
Visualizations like this one can help researchers focus on viral protein mechanics in an effort to develop drug molecules that can be used to prevent or treat dengue and other types of infection. For example, by targeting specific regions of proteins with small molecules designed to fit inside atomic grooves, normal folding patterns can be blocked and viral infection prevented.
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