The victims are tied with sticky threads, then the fatal attack follows: In order to capture and kill pathogens in the body, immune cells work together on the principle of web and spider, according to a study. Further insights into this antibacterial mechanism could help develop control strategies against stubborn pathogens such as Staphylococcus aureus, the scientists say.
Without our body police, all hell would break loose in the organism: Bacteria in particular are constantly lurking for their chance of infecting our tissues and then multiplying rapidly. The so-called hospital germs – antibiotic-resistant forms of staphylococci that can cause life-threatening infections, especially in immunocompromised people – are particularly notorious. Naturally, the bad guys are kept in check by the activity of various representatives of the immune cells, which also interact with one another in complex ways. The investigation of these systems is therefore of great importance for medical research.
The team led by Eric Skaar from Vanderbilt University in Nashville now focused on neutrophils and macrophages. Both are known as phagocytic cells – scavenger cells – which play an important role in fighting bacteria in the body. Earlier studies have already uncovered an interesting behavior in neutrophil granulocytes in their function as first aiders in the event of infection: the immune cells can destroy themselves when they come into contact with bacteria in order to release their DNA content. In the process known as NETosis, sticky threads form that act like a net trap to hold the pathogens in place. These neutrophil extracellular traps also contain antimicrobial agents. In order to effectively finish off the captured victims, however, an additional use of macrophages is apparently necessary, according to the results of Skaar and his colleagues.
A clever strategy in sight
As part of their study, the researchers carried out investigations in animal and in vitro model systems on special forms of neutrophil granulocytes that are particularly prone to the formation of net traps. The team first confirmed that the NETosis is a form of programmed cell death upon contact with bacterial pathogens: the neutrophils produce oxygen radicals particularly intensely when they encounter the pathogen Staphylococcus aureus. As a result, they break open and form the traps of DNA that they use to hold the enemies in place. However, as the further analyzes showed, the increased NETosis activity alone does not bring any advantages in the fight against the pathogens. Only through the cooperation with macrophages did the increased network formation show an effect.
According to the results, the combination of the antimicrobial peptides of the neutrophils with the activity of the macrophages leads to the death of the staphylococci. “The antibacterial arsenal of neutrophils apparently significantly expands the potential of macrophages,” explains Skaar. Ultimately, a kind of web-spider tactic is emerging, says the researcher: “Neutrophils produce the webs that make the bacteria immobile, and the macrophages then take on the role of the spiders that kill the bacteria”. As additional tests have shown, this cooperation is not limited to the fight against Staphylococcus aureus: the effects observed also occur with other bacterial pathogens. The results suggest that the cooperation between net-forming neutrophils and macrophages is a widespread mechanism in the immune defense, the researchers sum up.
Cooperation system with medical potential
As they further report, they also found evidence of an effect that could possibly be used medicinally: when they blocked a staphylococcal nuclease enzyme that cuts DNA, the bacteria trapped in the net became even more sensitive to being killed by the macrophages. “It seems as if pathogens like staphylococci have developed nucleases in order to be able to cut an escape route out of the nets,” says Skaar. This means that if you impair this bacterial strategy, you could support the immune system in eliminating the pathogens. Such strategies for reducing the virulence of bacteria can represent a promising alternative in the fight against pathogens. Because current pharmaceutical efforts are more focused on drugs like antibiotics that kill bacteria directly.
The scientists will therefore continue to research the NETose. Among other things, they want to investigate how and when the neutrophils “decide” for this form of programmed cell death. They are also interested in the extent to which NETose activity differs between people, for example due to genetic variations or diseases.
Source: Vanderbilt University, Science Advances, doi: 10.1126 / sciadv.abj2101