Researchers have uncovered how a trio of killer proteins in anthrax work together to invade cells.
A team of researchers led by Isabelle Rouiller of McGill University in Montreal, Canada built a 3-D map of the deadly spores and suggest three proteins form a conveyor belt of sorts that continuously shuttles lethal enzymes into a host’s cell.
The work was published in the Journal of General Physiology.
When a person eats, inhales or via broken skin is infected with spores produced by the anthrax-producing bacterium Bacillus anthracis, they’re assaulted by three proteins: lethal factor, oedema factor and protective antigen.
On their own, the proteins are pretty much harmless. But together, they bind to each other and make their way into host cells via “endosomes” – compartments made of cell membrane created to encapsulate extracellular molecules, for instance, for a cell to sort through.
Once inside an endosome, seven to eight protective antigen proteins then poke a hole in the endosome’s membrane, giving lethal factor and oedema factor a way in where they can damage, and perhaps kill, the host cell.
Rouiller and her colleagues wanted to find out what happened at this point.
Using electron microscopy at low temperatures (called cryo-electron microscopy) they built a 3-D “map” of the configuration formed by protective antigens and lethal factor at the pore just before protein invasion began.
Seven protective antigens surrounded the pore with three lethal factor proteins poised on the edge, ready to bust their way through.
Each lethal factor molecule clung to its neighbour – perhaps to keep them in position and stop them unfolding before it was time to do so.
Once the first lethal factor broke its grasp and dropped into the pore, its destabilised neighbour was hot on its tail. This meant the third also followed suit.
As they trickled through the pore, with protective antigens effectively holding the door open, other lethal factor molecules would take their place and be ferried through too.
This conveyor-belt-like process meant lethal factor could keep barrelling through quickly and efficiently, Rouiller says.
“The pore can effectively remain fully loaded for extended periods, acting as a conveyor belt while translocating a continuous ‘daisy chain’ of deadly [lethal factor] molecules.”
Together, protective antigen and lethal factor can be fatal. Add oedema factor to the mix and lethal factor becomes up to 100 times more potent.
And because anthrax proteins primarily target macrophages – immune cells that consume and destroy invading pathogens – they shut down the body’s defences if antibiotics aren’t administered in time, allowing the disease to rage unabated.