Genetic study maps bacteria’s protective armor behind severe infections

The first large-scale genetic study of E. coli's protective armor has identified the five capsule types that are responsible for 70 per cent of all multidrug-resistant bloodstream infections in Europe.

Researchers, including those at the Wellcome Sanger Institute, the University of Oslo, and their collaborators, analyzed over 18,000 bacterial genomes from samples across all continents to investigate E. coli's armor and find new ways to penetrate it.

The study, published today (25 March) in Nature Microbiology, uncovered 90 different types of protective capsules, of which only 34 per cent had been previously documented. The team also identified the capsule types that enable the bacterium to have the highest invasive potential, meaning it can transition from a harmless gut resident to a dangerous bloodstream invader.

By providing a blueprint of the armor that each E. coli strain has, this research can help in designing targeted vaccines and new treatments that can combat the most dangerous strains of E. coli while minimizing harm to beneficial strains of E. coli gut bacteria.

Escherichia coli (E. coli) is the leading cause of bloodstream infections worldwide¹. Most strains of E. coli are harmless and commonly found in the gut, however, if the bacterium gets into the bloodstream or the urinary tract, it can cause infections that range from mild to severe, particularly in people with a weakened immune system.

As an added challenge for healthcare providers, antibiotic resistance has become a frequent feature of such infections. Rates of antibiotic resistance in E. coli vary globally and, in the UK, over 40 per cent of E. coli bloodstream infections are resistant to a key antibiotic².

Some bacteria, such as E. coli, have protective capsules that help shield the bacteria from the immune system and certain treatments, influencing the bacteria's ability to cause infections. Each bacterial strain has a different capsule makeup, and the capsules have markers, called antigens. These antigens are often used as targets for new vaccines and treatments. However, for effective therapies to be developed, researchers need to know which capsule commonly causes the infection.

Traditional methods of mapping E. coli capsules are labor-intensive and uncommon. To address this, the team at the Sanger Institute and their collaborators genetically analysed 18,000 E. coli samples. This allowed them to create the first digital database mapping capsule type and E. coli strain. They were then able to determine how common each type is using samples from nearly 8,000 people, ranging from newborns to those over 80 years old.

They found that capsule types are much more diverse than previously thought, mapping 90 different types, including 69 that had not been previously documented. The team also noted that different capsules were common in high-resource settings, such as the UK, compared to less industrialised regions such as Malawi and Pakistan.

For example, the researchers found that five specific capsule types (K1, K5, K52, K2, and K14) account for over 50 per cent of all E. coli bloodstream infections and urinary tract infections across the UK, Norway, and France. Furthermore, a slightly different set (K1, K5, K52, K2, and K100) is responsible for 70 per cent of multidrug-resistant E. coli infections in Europe. While two of these (K1 and K5) do cause infections globally, there is more diversity in the strains that cause serious infections in low and middle-income countries than in Europe.

Due to these differences, the researchers highlight the importance of global data in future research, especially around drug and vaccine development, as the bacterial capsule types being targeted would vary depending on where the individual lived.

The team also found that E. coli has the ability to swap the genes that encode the capsule, sharing the information to build different types of armor between them.

By creating a digital library from over 18,000 bacterial genomes, we can see the true complexity of how E. coli protects itself, and how this armor is encoded in the genes. This research has expanded our scientific map from just a handful of known bacterial shields to a comprehensive database of 90 unique types, including nearly two-thirds that were previously unknown. Ultimately, this database provides the missing blueprint to identify strains most likely to cause serious infections, and design targeted vaccines and treatments to stop these."

Dr. Rebecca Gladstone, first and corresponding author, University of Oslo

Professor Jukka Corander, senior author at the Wellcome Sanger Institute and the University of Oslo, said: "This new research enables us to identify the strains of E. coli that are the biggest threats to human health. With this database, we can now see the bacterial capsule types that are prevalent in different countries, whether they cause serious infections, or if they are resistant to treatments. What our research also shows is the stark differences between capsule groups found in different regions, highlighting the need for systematic and standardised global data collection. Especially as we have found that E. coli can trade the genes for their protective shields between different genetic lineages. Understanding how these bacteria, especially the most drug-resistant ones, swap their coats, and having the global data to track this, is crucial for staying one step ahead of them in the fight against serious bloodstream infections."

Dr Trevor Lawley, co-author at the Wellcome Sanger Institute, said: "Our microbiomes are made up of thousands of bacteria, and while the majority of these are beneficial, some strains can cause infections if they get into the bloodstream, such as E. coli. Large-scale population studies, such as the Baby Biome study, that provide a high-resolution view into the microbiome are essential for understanding the risk associated with certain bacterial strains, the genetic tools they use to cause infections, and how often they are found in the population. Understanding and tracking the E. coli strains that are most able to use their protective shield to move into the bloodstream and cause infection allows for the development of future targeted treatments while minimising the harmful effects on the microbiome."