With the rise in antibiotic drug resistance, alternative and complementary methods to treating bacterial infections are essential. A team of investigators at Lund University in Sweden and the University of Copenhagen may have a potential alternative therapy for at least one serious infection (pneumococcal meningitis) that can lead to life-threatening sepsis. Insights from this new study—published today in Nature Communications through an article titled “Neutrophil extracellular traps in the central nervous system hinder bacterial clearance during pneumococcal meningitis”—could open the door to novel treatments for other bacterial infections.
The human immune system has several important defenders to call on when an infection affects the central nervous system. In the current study, the researchers mapped what happens when one of them—neutrophils—intervenes in bacterial meningitis. If there is an infection, neutrophils deploy to the infected area in order to capture and neutralize the bacteria. It is a tough battle and the neutrophils usually die, but if the bacteria are difficult to eliminate, the neutrophils resort to more drastic tactics.
“It is as though in pure frustration they turn themselves inside out in a desperate attempt to capture the bacteria they have not been able to overcome,” explained senior study investigator Adam Linder, associate professor at Lund University and specialist in infectious diseases at Skåne University Hospital. “Using this approach, they capture a number of bacteria at once in net-like structures, or neutrophil extracellular traps (NETs). This works very well in many places in the body where the NETs containing the captured bacteria can be transported in the blood and then neutralized in the liver or spleen. However, in the case of bacterial meningitis these NETs get caught in the cerebrospinal space, and the cleaning station there is not very effective.”
Using advanced microscopy, the research team observed that the cerebrospinal fluid from patients with bacterial meningitis was cloudy and full of lumps, which proved to be NETs. However, among patients with viral meningitis, the cerebrospinal fluid was free from NETs. When captured bacteria get caught in the cerebrospinal fluid, this adversely affects the immune system’s work of clearing away bacteria and impedes standard antibiotics from getting at the bacteria.
In an attempt to determine if exposing the “netted” bacteria to the immune system and antibiotics could be a viable treatment intervention, the researchers investigated what would happen if in drugs used for digesting DNA, such as DNase, were utilized—since the bulk of NETs consists of a DNA meshwork.
“We gave DNase to rats infected with pneumococcus bacteria, which caused bacterial meningitis, and could show that the NETs dissolved, and the bacteria disappeared,” noted lead study investigator Tirthankar Mohanty, PhD, a postdoctoral fellow at Lund University. “It seems that when we cut up the NETs, the bacteria are exposed to the immune system, which finds it easier to combat the bacteria single-handed. We were able to facilitate a significant reduction in the number of bacteria without antibiotic intervention.”
Interestingly, in the 1950s, professor William Tillett, while at The Rockefeller University, found lumps in the CSF of patients with bacterial meningitis. Tillett discovered that these lumps could be dissolved using DNase. This was effective in combination with antibiotics and reduced the mortality rate for meningitis from around 30% to about 20%. However, this treatment had side effects, as the DNase was extracted from animals and could, therefore, trigger allergic side effects.
“At that time, everyone was so happy about the antibiotics, they reduced mortality for the infections, and it was thought that we had won the war against bacteria,” Linder states. “I believe we need to go back and take up a part of the research that took place around the time of the breakthrough for antibiotics. We can perhaps learn from some of the discoveries that were then flushed down the drain.”
Based on their current findings, the researcher’s are looking to set up a major international clinical study and use DNase in the treatment of patients with bacterial meningitis.
“The development of resistance in bacteria is accelerating and we need alternatives to antibiotics. The drug we use in the studies is a therapeutic biological product derived from humans and has already been approved for human use,” concluded Mohanty. “They are not expensive and have also been tested against many different bacteria and infections. Bacterial meningitis is a major challenge in many parts of the world. In India, for example, it is a major cause of death among children, so there would be significant benefits there for using such a treatment strategy.”