To kill bacteria in the blood, our immune system relies on nanomachines that can open deadly holes in their targets. We have now filmed these nanomachines in action, discovering a key bottleneck in the execution of their killer function, which helps to protect our own cells.
Our research, published in Nature Communications, provides us with a better understanding of how the immune system kills bacteria and of why our own cells remain intact. This may guide the development of new therapies that harness the immune system against bacterial infections, and strategies that repurpose the immune system to act against other rogue cells in the body.
In earlier research, published in EMBO Journal earlier this year, we had imaged the hallmarks of attack on live bacteria, showing that the immune system response results in ‘bullet holes’ spread across the pathogen’s cell envelopes. The holes are incredibly small with a diameter of just 10 nanometres – about 1/10,000 of the width of a human hair.
To film this process in real time, we mimicked how these deadly holes are formed by the membrane attack complex (MAC) using a model bacterial surface. By tracking each step of the process, we found that shortly after each hole started to form, the process stalled, offering a reprise for the body’s own cells.
“It appears as if these nanomachines wait a moment, allowing their potential victim to intervene, in case it is one of the body’s own cells instead of an invading bug, before they deal the killer blow,” explained Dr Edward Parsons, first author of this study and postdoc in our lab. The process pauses as 18 copies of the same protein are needed to complete a hole. Initially, there’s only one copy which inserts into the bacterial surface, after which the other copies of the protein slot into place much more rapidly.
“It is the insertion of the first protein of the membrane attack complex which causes the bottleneck in the killing process. Curiously, it coincides with the point where hole formation is prevented on our own healthy cells, thus leaving them undamaged,” said Professor Bart Hoogenboom.
To film the immune system in action at nanometre resolution and at a few seconds per frame, we used atomic force microscopy. This type of microscopy uses an ultrafine needle to feel rather than see molecules on a surface, similar to a blind person reading Braille. The needle repeatedly scans the surface to produce an image that refreshes fast enough to track how immune proteins get together and cut into the bacterial surface.
The research was carried out in close collaboration with scientists from Imperial College London, from the Swiss Federal Institute of Technology in Lausanne, and from the University of Leeds; and for the work on bacteria, we relied on a collaboration with the University Medical Centre Utrecht.
The work was kindly funded by the Biotechnology and Biological Sciences Research Council, Medical Research Council, Engineering and Physical Sciences Research Council and the European Union.