With the increasing threat of antibiotic resistance, there is a growing need for new treatment strategies against life threatening bacterial infections. Researchers at Lund University in Sweden and the University of Copenhagen may have identified such an alternative treatment for bacterial meningitis, a serious infection that can lead to sepsis.
Lund/Sweden — Our immune system has several important defenders to call on when an infection affects the central nervous system. The researchers have mapped what happens when one of them, the white blood cells called neutrophils, intervene in bacterial meningitis.
If there is an infection, the neutrophils deploy to the infected area in order to capture and neutralise the bacteria. It is a tough battle and the neutrophils usually die, but if the bacteria are difficult to eliminate, the neutrophils resort to other tactics. They turn themselves inside out in an attempt to capture the bacteria they have not been able to catch. 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 neutralised in the liver or spleen, for example. However, in the case of bacterial meningitis these NETs get caught in the cerebrospinal space, and the cleaning station there is not very effective.
Researchers observed, by using advanced microscopy; that the cerebrospinal fluid of 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 also impedes standard antibiotics from getting at the bacteria, says Adam Linder.
Would it be possible to cut up the nets so that the bacteria are exposed to the body’s immune system, as well as to antibiotics, making it easier to combat the infection? As the NETs consist mainly of DNA, the researchers investigated what would happen if you brought in drugs used for cutting up DNA, so-called DNase.
“We gave DNase to rats infected with pneumococcus bacteria, which caused bacterial meningitis, and could show that the NETs dissolved and the bacteria disappeared. 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, says Tirthankar Mohanty, one of the researchers behind the study.
Before antibiotics, the mortality rate for bacterial meningitis was around 80 %. With the advent of antibiotics, the mortality rate quickly fell to around 30 %.
In the 1950s, Professor Tillett at the Rockefeller University in the USA, found lumps in the cerebrospinal fluid of patients with bacterial meningitis. Professor 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 happy about antibiotics as they reduced mortality for the infections and it was thought that bacteria were defeated. Adam Linder believe that we need to go back and take up a part of the research that took place around the time of the breakthrough for antibiotics. In this way it could be possible to learn from some of the discoveries that were ignored.
The researchers want to go on to set up a major international clinical study and use DNase in the treatment of patients with bacterial meningitis.
Reference: Neutrophil extracellular traps in the central nervous system hinder bacterial clearance during pneumococcal meningitis; DOI: 10.1038/s41467-019-09040-0