Australian scientists have discovered a previously unknown protective mechanism bacteria use to kill immune cells, opening up potential research pathways that could help doctors fight antibiotic-resistant superbugs.
When the body detects a bacterial infection, one of its defense mechanisms is to release immune cells such as macrophages, which hunt for pathogens, then engulf and destroy them. But the bacteria can fight back, releasing a number of different toxins to target immune cells, many of which are well known and common targets for anti-superbug research – if we can work out how to block these toxins and disarm the bacteria's defenses, we're on the way to fighting antibiotic-resistant bugs.
Now, researchers from the Biomedicine Discovery Institute at Monash University say they've uncovered a "secret weapon," finding a new method by which the bacteria attack macrophages, releasing a previously unknown endotoxin that activates cell death factors in the immune cells, eventually shutting down their mitochondria and triggering a kind of cellular suicide called apoptosis.
Using three bacterial pathogens – Neisseria gonorrhoeae, uropathogenic E.coli and the deadly Pseudomonas aeruginosa, which is prevalent in hospitals and can be drug resistant – the researchers genetically targeted factors involved with apoptosis, and found they were able to reduce inflammation in mice, leading to better health outcomes.
“There’s been a lot of effort trying to block endotoxins that kill immune cells but this study really shifts the focus onto different toxins that might be more important,” said Dr. Thomas Naderer, whose lab produced the research. “It gives us a few good leads that we can look at as a next step. We’ve shown in this paper that we can accelerate the immune response. The other side is that if that response persists and we get constant inflammation – which is usually associated with bacterial infection and which causes a lot of tissue damage – we have a new way to shut down that tissue-damaging inflammation.”
“What scientists have thought before is that when endotoxins are released by bacteria they induce an inflammatory type of programmed cell death called pyroptosis in immune cells,” added Dr. Pankaji Deo, first author on the study. “We’ve found that the pathogenic bacteria use a similar mechanism to release additional toxins. They kill immune cells by releasing small surface structures called outer membrane vesicles – packages of toxins that target mitochondria. The mitochondria are disarmed, become dysfunctional then die according to apoptosis or cellular suicide.”
The next step is to test drugs that are advancing to clinical use, as well as other drugs that are already approved for use in other treatments, including anti-cancer drugs, to see if they can successfully target these newly found mechanisms and help clear out bacterial infections.
The research was published in Nature Microbiology.
Source: Monash University via Scimex