Rotavirus, a major cause of early childhood diarrhea, could have a lot to tell drug developers about how to deliver their products into cells.
Rotavirus doesn’t have an outer membrane, so it’s had to evolve a special system to infect cells. “Viruses with a membrane, like flu or HIV, can simply fuse that membrane with the membrane of the target cell and dump their contents inside the cell,” says Stephen Harrison, PhD, chief of the Laboratory of Molecular Medicine at Boston Children’s Hospital.
Rotavirus does something different, Harrison’s lab has found. First, each virion attaches itself to the cell membrane and wraps itself inside it. Next, its outer proteins, VP4 (the red spikes above) and VP7 (in yellow), disrupt that membrane — and are stripped off in a matter of seconds.
“If you will, they’re the booster the rocket has to shed so the payload can continue,” says Harrison.
That payload, the core rotavirus particle shown in green, is then released into the cell’s interior, where it proceeds to the end game: making the RNA it needs to replicate itself.
Harrison and colleagues followed the action by replacing the outer proteins with engineered, fluorescently tagged replicas. They also tagged the core particle. In this way, they could tell which particles were uncoated and released into the cell and which remained wrapped in the cell membrane. Additional probes allowed them to detect which rotavirus core particles were synthesizing RNA.
Not perfect, but sufficient
Once they attached to cells, only 20 to 50 percent of rotavirus particles were able to strip off their exterior proteins. Of these uncoated particles, only 10 percent successfully made RNA.
But for rotavirus, that’s enough.
“Even just one particle making RNA in a cell is enough to initiate an infection,” Harrison says. “Just like it takes only one sperm of millions to fertilize an egg, evolution doesn’t necessarily care about efficiency at that level.”
Because rotavirus can easily be manipulated, Harrison thinks its method of infiltrating cells may inform new ways of delivering therapeutics. “Whether this mechanism will prove useful is harder to stay, but we have to know the natural rules of the game in order to imitate them,” he says.
Their findings appeared in the Journal of Virology.