Chikungunya virus, once confined to the Eastern Hemisphere; has infected more than 1 million people in the Americas since 2013 when mosquitoes carrying the virus discovered in the Caribbean. Most people who become infected develop a fever and joint pain that last about a week. But in up to half of patients; the virus can cause severe arthritis that persists for months or years. There is no treatment to prevent the short-lived infection from persisting into chronic arthritis.
Chikungunya arthritis comes on very suddenly and can very painful people can barely walk around and they have nothing specific to treat or prevent. Now that we have these new structures, they can see how to disrupt the interaction between the virus and the protein it uses to get inside cells in the joints and other musculoskeletal tissues in order to block infections,” added co-senior author Daved Fremont; professor of pathology and immunology; of biochemistry and molecular biophysics, and of molecular microbiology.
In 2018, Diamond, Fremont, and colleagues including postdoctoral researcher Rong Zhang identified the protein Mxra8; which is on the outer surface of cells in the joints; as the molecular handle that chikungunya and related viruses grasp to gain entry into cells of mice, humans and other species. The human and mice versions of Mxra8 are 79 % identical; chikungunya virus interacts with both versions in the same way.
The chikungunya virus
Viruses need to latch onto the protein to cause disease; in mice, thwarting chikungunya’s attempts to attach to the protein using blocking antibodies or decoy receptors reduced signs of arthritis. Images obtained using a chikungunya virus-like particle which has the shape of a virus but cannot cause infections; because it carries no genetic material inside as well as a fully infectious chikungunya virus. The virus-like particles are being evaluated in clinical trials as a potential vaccine for chikungunya.
To visualize how the virus interacts with the cell-surface protein, the researchers first flash-froze the viral particles attached to the protein. The snap freeze was necessary to keep the particles from being destroyed during the experiment. Then, the researchers shot a beam of electrons through the sample; mapped where the electrons landed on a detector and used computer programs to reconstruct the electron density patterns and thereby the 3-D structure of the viral particles bound to the cell-surface protein.
The high-resolution structure will aid efforts to screen experimental drugs; for their ability to block attachment to the protein on cells in the joints; evaluate whether the antibodies elicited by investigational vaccines are likely to prevent infection, and analyze whether mutations in viruses affect their virulence.