How the immune system kills bacteria
Snapshots of hole formation in a bacterial surface [Edward S. Parsons et al]
UK-based researchers have used rapid atomic force microscopy to image the immune system protein assembly, known as the membrane attack complex, that can open deadly holes in target pathogens.
As part of their research into the single-molecule kinetics of pore assembly, Dr Edward Parsons and Professor Bart Hoogenboom, University College London, discovered a bottleneck in this perforation process that helps to protect the body's own cells.
The results shed new light on how the immune system kills bacteria, why our own cells remain intact and opens the door to new therapies help the immune system to fight bacterial infections and rogue cells in the body.
Membrane attack complexes, imaged on the back of a bacterium. The scale bars correspond to 800 (left) and 30 (right) nanometres. [EMBO Journal (2019), Dani AC Heesterbeek et al.]
In earlier research, the researchers imaged the hallmarks of attack in live bacteria, showing that the membrane attack complex perforates holes, some 10 nm in diameter, across the cell envelopes of bacteria.
In the latest study, the researchers mimicked hole formation via the membrane attack complex using a model bacterial surface.
As the researchers describes in Nature Communications, different stages of hole formation were imaged, via AFM, in fluid using either a Bruker Dimension FastScan, a Bruker BioScope Resolve or a home-built instrument with rapid imaging capabilities.
Video sequence of the formation of a hole in a bacterial surface, recorded at 6.5 seconds per frame. The scale bar (see first frame) corresponds to 30 nanometres. [Edward S. Parsons et al. UCL]
Imaging was generally performed in off-resonance tapping/fast force-feedback imaging - Bruker’s PeakForce Tapping – mode with images collected at 5–100 s/frame.
By tracking each step of the process in this way, they found that shortly after each hole started to form, the process stalled, offering a reprise for the body's own cells.
According to the Parsons, the process pauses as 18 copies of the same protein are needed to complete that hole.
Initially, only one protein copy is inserted into the bacterial surface, and then the additional copies slot into place more rapidly.
Holes forming. [Edward S. Parsons et al. UCL]
"It is the insertion of the first protein of the membrane attack complex which causes the bottleneck in the killing process,” highlights Hoogenboom. “Curiously, it coincides with the point where hole formation is prevented on our own healthy cells, thus leaving them undamaged."
Research is published in Nature Communications.