The word “chikungunya” (chik-en-gun-ye) comes from Kimakonde, the language spoken by the Makonde people in southeast Tanzania and northern Mozambique. It means “to become contorted,” because that’s what happens to people who get infected. The contortion is a result of severe and debilitating joint pain. Chikungunya was first identified in Tanzania in 1952, but by now cases have been reported around the globe. There is no cure; the CDC recommends that “travelers can protect themselves by preventing mosquito bites.”

Chikungunya is only one of a family of viruses transmitted through mosquitoes for which we have no targeted treatment. This may partially be due to the fact that we didn’t know how they get into our cells. But for chikungunya, we've just found one of the proteins responsible.

Identification via deletion

Researchers used the CRISPR-Cas9 DNA editing system to delete more than twenty-thousand mouse genes—a different one in each cell in a dish. Then they added chikungunya to the dish, isolated the cells that didn’t get infected, and looked to see which gene they lacked. This gene would encode a protein required for viral infection, since infection didn’t happen in its absence.

In this way they found a gene encoding an adhesion molecule that was required for chikungunya to infect these cells. Similar genes are found in other mammals, birds, and amphibians, and they are homologous to an adhesion molecule used as an entry receptor for another class of viruses. This particular gene goes by the catchy name of Mxra8. Interestingly, no similar protein is found in mosquitoes.

Since the scientists were using a special “cell-culture-adapted vaccine strain” of chikungunya, they repeated their experiment with an Asian strain and a West African strain of the virus. Neither could infect cells lacking Mxra8. Nor could some other viruses in the same family (called arthritogenic alphaviruses): Ross River virus, Mayaro virus, Barmah Forest virus, and O’nyong nyong virus. However, an East/Central/South African strain of chikungunya and a few others in the same family did not seem to be quite as dependent on Mxra8.

In human cells, too

Results were not limited to mouse cells in petri dishes. They also held true in human cells of the various types infected by chikungunya, like fibroblasts, osteoblasts, chondrocytes, and skeletal muscle cells. Humans have four versions of Mxra8, and knocking out each of them diminished the ability of chikungunya to infect the cells. Mice treated with antibodies to Mxra8 had reduced levels of infection—the antibodies bind to the Mxra8 molecules on the surface of the mouse cells, so the virus can’t access it to get in.

Mxra8 doesn’t seem to be required for viral replication, only for viral entry into cells. Further experiments that home in on exactly where the virus binds to it could hopefully lead to the development or identification of small molecules that block the interaction, barring the virus from getting into the cells and preventing infection and disease.

Nature, 2018. DOI: 10.1038/s41586-018-0121-3 (About DOIs).