Gene Against Bacterial Attack is Unraveled

Dutch researcher and physician Joost Wiersinga from AMC Medical Centre in Amsterdam has unraveled a genetic defense mechanism against the lethal bacteria Burkholderia pseudomallei. The research is the next step toward a vaccine against this bacterium suitable for bio-weapons.

Humans have an innate defense system against deadly bacteria. However, how the step from gene to antibacterial effect occurs in the body is not yet known. To date, B. Pseudomallei, a bacterium suitable for bio-weapons, had managed to elude medics. It can remain hidden in the human body for many years without being detected by the immune system. The bacteria can suddenly become activated and spread throughout the body, resulting in the patient dying from blood poisoning. Wiersinga and the Laboratory for Experimental Internal Medicine discovered which gene-protein combination renders the lethal bacteria B. pseudomallei harmless.

Wiersinga focussed on the so-called toll-like receptors, the proteins that initiate the fight against pathogens. There are currently 10 known toll-like receptors which are located on the outside of immune cells, our body's defense system. The toll-like receptors jointly function as a 10-figure alarm code. Upon coming into contact with the immune cell each bacterium enters its own toll code. For known pathogens this sets off an alarm in the immune system and the defense mechanism is activated. Yet B. pseudomallei fools the system by entering the code of a harmless bacterium. As a result the body's defense system remains on standby.

Yet some people are resistant: they become infected but not ill. Wiersinga found a genetic cause for this resistance. He discovered which toll receptor can fend off B. pseudomallei. He did this by rearing mice DNA in which the gene for Toll2 production was switched on and off.

“The group where the gene for Toll2 was switched off, survived the bacterial infection,” says Wiersinga. “The other receptor that we investigated, Toll4, had no effect - even though for the past 10 years medics had regarded this as the most important receptor.” The ultimate aim of this study is to develop a vaccine.

Wiersinga and his colleagues are working together with the Wellcome Trust in Oxford and a clinic in Thailand. B. pseudomallei is endemic in Asia and claims thousands of victims each year. The research was published in PloS Medicine, and Science and Nature Reviews also ran articles on it. NWO funded the work.