New images may improve vaccine design for deadly rotavirus

Howard Hughes Medical Institute researchers are reporting the first detailed molecular snapshots of a deadly gastrointestinal virus as it is caught in the grasp of an immune system molecule with the capacity to destroy it. The images could help scientists design a more effective vaccine against rotavirus, a lethal infection that kills more than 500,000 children worldwide each year. The discovery is timely.

Last week the World Health Organization recommended that rotavirus vaccination be included in all national immunization programs worldwide. Virtually every child in the world becomes infected with rotaviruses before developing natural immunity. But each year an estimated two million children are hospitalized because rotavirus infection results in severe dehydration caused by diarrhea and vomiting.

Both natural and vaccine-induced immunity occur only after the immune system has "seen" the virus and generates neutralizing antibodies. These soldiers of the immune system seek out and attach to rotavirus particles, rendering them unable to infect cells.

In the new experiments, Howard Hughes Medical Institute (HHMI) researchers have mapped the structure of an antiviral antibody clamped onto a protein called VP7 that stipples the surface of rotavirus. The structural map reveals intimate new details about how the antibody interferes with VP7, a protein that helps the virus infect cells. The information may be useful in designing a new generation of rotavirus vaccines that could be easier to store and administer than current vaccines, said the researchers.

HHMI investigator Stephen C. Harrison and colleagues at Children's Hospital Boston and Harvard University published their findings in the June 12, 2009, issue of the journal Science.

Rotaviruses replicate mainly in the gut, where they infect cells in the small intestine. The virus has a triple-layered protein coat, which allows it to resist being chewed up by digestive enzymes or the gut's acidic environment. Rotavirus does not have an envelope covering its protein shell. A virus' envelope helps it enter host cells, and viruses without envelopes face significant hurdles in penetrating the membrane of the cells they infect. "Since they have no membrane of their own, they must therefore perforate a cellular membrane to gain access to the cytoplasm (the interior of the cell)," he said.

The new research shows that as rotavirus matures inside an infected cell, it assembles a kind of "armor" coating made principally of VP7 and a "spike" protein called VP4. When the mature virus particle exits one cell to infect a new cell, it perforates the endosomal membrane of the target cell by thrusting in its VP4 spike like a grappling hook.