Newborn meningitis is one of the most dangerous childhood infections. It is often life-threatening and can cause serious and lasting damage, including developmental problems, in the children who survive. Although meningitis is thankfully rare in newborns as a whole, it is more common in premature babies, affecting one in every 500 such infants in industrialised economies and likely more in developing countries.
One of the leading pathogens responsible for these meningitis cases is the K1 form of the E. coli bacterium. Now, researchers from ETH Zurich and the University of Basel have developed an approach that seeks to prevent transmission to newborns.
To understand this approach, we need to start in the adult intestine: in one in three healthy adults, E. coli K1 is part of the intestinal flora. As a silent cohabitant, the bacterium causes no problems in this environment. It is kept in check by other bacteria and a functioning immune system.
However, if the pathogen is carried by an expectant mother, it can be transmitted to the child during birth and enter its intestine. In premature babies whose immune systems are still weak, the pathogen can enter the bloodstream and migrate to the brain, where it causes severe inflammation.
First weaken the pathogen, then fight it
Researchers led by Emma Slack, Professor of Mucosal Immunology at ETH Zurich, and Médéric Diard, Professor of Infection Biology at the Biozentrum of the University of Basel, want to stop transmission from happening in the first place. Their idea is to eliminate the pathogen in pregnant women who carry it in their intestine – but that's easier said than done.
A year ago, the two researchers from Zurich and Basel had already jointly developed a concept for eradicating other pathogens living in the intestine (as ETH News reported ). Back then, they used a combination therapy with two components: an oral vaccination that weakens the pathogenic bacterium, followed by a dose of harmless microbes that compete with the weakened pathogen for food, starve it out, and ultimately supersede it. In experiments on mice, the researchers demonstrated that this approach can eliminate certain salmonellas and E. coli strains in the intestine.
So tough that three components are needed
However, the K1 form of E. coli is a formidable opponent: unlike other E. coli bacteria, it is protected by a slippery outer layer. This prevents the antibodies generated by the oral vaccination from attacking the bacterium.
The team of researchers led by Slack and Diard therefore extended its previous two-pronged approach with a third component known as bacteriophages (or simply phages). These are viruses that specifically infect and kill bacteria.
However, the bacteria can make changes to themselves in order to evade the danger posed by these viruses. The phages attack the bacteria by docking to the protective layer, and the bacteria seek to prevent this by undergoing a sort of rapid evolution in which this layer is disposed of. Rapid in this case means that, since the bacteria are so numerous and multiply so quickly, they need fewer than 24 hours to adapt.
"This is essentially a resistance mechanism that the bacteria deploy against the phages," says Slack. "We use this mechanism to our advantage: the antibodies formed by the oral vaccination are effective against K1 bacteria that no longer have their protective coating."
Most young animals protected
The project involved searching for effective strains of phages. Scientists generally find phages in places that are home to lots of bacteria: nutrient-rich bodies of water, the intestinal flora or, very often, waste water and waste water treatment plants. When it comes to the phages used in this study, the researchers from the Biozentrum in Basel found what they were looking for in waste water samples from the treatment plant of the Lucerne conurbation. From such a sample, their lab work successfully isolated several phages that are particularly effective at attacking the bacterium E. coli K1.
In experiments with pregnant mice, which the researchers had previously infected with pathogenic E. coli K1, they were able to demonstrate the effectiveness of their triple-pronged treatment. The researchers first gave the mice phages that forced the bacteria to cast off their protective shell. Second, they administered an oral vaccination that produced antibodies in the intestine in order to weaken the bacteria. Third, they gave them a harmless probiotic bacterium that could compete against the weakened bacteria and occupy their ecological niche in the intestine.
In a control experiment in which the researchers did not treat the mothers, E. coli K1 was transmitted to 83 percent of young animals at birth. By contrast, the triple-pronged treatment significantly reduced the level of E. coli K1 in the mothers' intestines, such that the pathogen was only transmitted to 23 percent of the young animals. The remaining offspring were protected.
Works even when antibiotics fail
The researchers are now keen to continue with their approach in order to develop a treatment for humans. In a world in which effective antibiotics are becoming increasingly scarce, we need new therapeutic approaches, says Slack. "Bacteria such as E. coli K1 are difficult to tackle. Our approach is potentially the only one that can be used to fight this pathogen and others without antibiotics."
Not only can E. coli K1 cause cases of meningitis in newborns, which today must be treated with antibiotics in a race against time. It is also one of the most frequent causes of cystitis and pyelitis – infections that can also lead to serious cases of sepsis.
The ETH professor doesn't perceive any major obstacles to developing an effective treatment for humans: "Oral vaccinations, probiotics and even phages are all already used in medicine," she says. It will also be possible, she adds, to pack all three components into a single capsule that people can simply swallow.
Moreover, the scientists are planning projects in which they want to use the same approach to tackle bacteria other than E. coli K1, including multi-resistant pathogens, against which many antibiotics are no longer effective.
This research project was supported by the Basel Research Centre for Child Health.
