Toronto, ON – Cloaked and armed with a weapon, Listeria monocytogenes bacterium invades the cells of its host during infection, where it can replicate. The bacterium then spreads from cell to cell by exploiting one of the bodies’ own defense mechanisms, says new research led by the Hospital for Sick Children (SickKids) and published in the April 13 online edition of Nature.
The mechanism called efferocytosis is a normal housekeeping function of all cells and is a process by which cellular garbage (dead cells) is eaten up by neighbouring cells. It is estimated that more than 50 billion cells in our body die every day. Cellular garbage can cause inflammation, so this housekeeping function is a very important part of regulating the body’s internal environment.
Researchers found that in order to spread from cell to cell, Listeria disguises itself as cellular garbage so that other cells will eat it. Once inside the neighbouring cell, Listeria removes its disguise, releases its toxin and can freely replicate inside the cell.
“Prior to this research we didn’t appreciate that Listeria was able to exploit a normal housekeeping function to promote its spread during infection. We’ve uncovered what I call a ‘cloak and dagger’ story. Our research shows how Listeria found a weak point in our armour and took advantage of it,” says Dr. John Brumell, senior scientist in cell biology at SickKids.
There are antibodies and other immune defenses in the fluid space between cells that protect tissues from infection. By invading into the cells, Listeria can evade these defenses and this allows them to replicate rapidly, doubling their numbers in as little as 40 minutes. Researchers found that for Listeria to move to another cell, it creates a chemical reaction to rocket out of the cell. Because of this large force used to exit the cell, the bacterium is cloaked in the membrane of the cell it just left. This membrane cloak disguises Listeria as cellular garbage as it waits for a neighbouring cell to eat it up, says Brumell.
The results are surprising since efferocytosis was thought to be an immune defense, he adds. Previous research on Mycobacterium tuberculosis, the bacterium that causes tuberculosis (TB), has shown that efferocytosis can be used to kill bacteria. When TB infects macrophages, which are specialized cells of the immune system designed to target and destroy infection, the macrophages recognize the TB bacterium, eat it and self-destruct with the bacterium inside. Then through efferocytosis the neighbouring cells help out by eating the cellular garbage eliminating what may remain of the TB bacteria. In this case, efferocytosis effectively kills the bacteria.
“It’s the opposite for Listeria. The bacteria use efferocytosis as a way to get into the neighbouring cells. Once inside and before it can be broken down as garbage, Listeria uses its dagger, the pore-forming toxin called listeriolysin O, to break out of the cloaked membrane and infect the cell,” says Brumell, who is also professor in the Institute of Medical Science and Department of Molecular Genetics at the University of Toronto.
Brumell and his team continue to investigate the basic mechanisms of how bacteria can spread and will be looking more closely at the process of efferocytosis to try and find new therapeutic targets to protect against the spread of bacteria. Brumell adds that there are other bacteria that use a similar strategy for cell-to-cell spread, so finding out things that work for Listeria could be very important for other diseases as well.
“To be effective and cause disease, every bacterial pathogen has to be able to spread within our bodies. While our research shows how Listeria has uncovered one of our weaknesses, its need to spread is its own key weakness. If we can learn how to block bacterial spread with new drug therapies, we can block disease,” says Brumell. “There were many steps leading up to this finding, and we have many more steps to take.”
The study was funded by The Arthritis Society of Canada.