New clues point to a protective shield that could change harmless bacteria into killers

• Neisseria meningitidis (meningococcal bacteria) is a leading cause of meningitis. 
• As many as 1 in 10 of us carry it harmlessly in the back of the nose and throat, but it can occasionally turn lethal – why this happens is poorly understood.
• The research helps shed light on genes responsible for a shield-like capsule that could help protect some bacteria from our immune system, making them deadly.

Researchers from the Karolinska Institutet in Sweden, are helping to explain why bacteria that often live harmlessly in the back of the nose and throat can turn lethal and cause meningitis. They compared the genetic code from thousands of samples and found differences in the cellular machinery responsible for producing this bacterium’s capsule coating. They identified specific subtle genetic changes which produced shield-like ‘hypercapsulation’ surrounding the bacterium that could improve its survival against our immune system.
 
The research, published in the journal Lancet Microbe, found that the presence of this hypercapsulation was almost twice as high among the bacteria which caused serious diseases compared to the bacteria which was harmlessly carried. The findings could help produce rapid tests to identify the risk of severe infection.
 
Neisseria meningitidis (meningococcal bacteria) is a leading cause of meningitis. As many as 1 in 10 of us carry the bacteria harmlessly in the back of the nose and throat, but they can occasionally turn lethal. The mechanisms of how these bacteria shift to causing severe infection are poorly understood.
 
This new research compared the genes of the cellular machinery responsible for producing the bacterium’s outer shell – the capsule. The bacterial capsule is a large structure made of complex sugars (polysaccharides) that forms part of the outer envelope of a bacterial cell. It is one of the bacteria’s main defences against the human immune system.
 
The researchers found that some bacteria produced more capsule than others – hypercapsulation – which acts as a shield against our immune system. They found that increased capsule production was associated with higher survival rates in human blood serum.
 
A temperature-sensitive molecule called an RNA thermosensor (RNAT) controls the production of this capsule. The researchers compared over 7000 samples of meningococcal bacteria looking at differences in these RNATs. They discovered five new variations of this RNAT which led to hypercapsulation, and so better protection inside the human body. The prevalence of these variant RNATs was almost twice as high in bacteria that cause diseases compared with ones that are harmlessly carried. 

The research work was initiated in 2017 after a strain of the Neisseria meningitidis bacterium was isolated from a Swedish teenager who succumbed to severe illness. When compared with a sample from an individual from the same outbreak who did not get ill, they discovered the only notable difference between the two samples was the genetic change in the RNAT. This prompted the researchers to further investigate the association of this RNAT mutation to severe meningitis.
 
“We are now working on a simple and quick test that could help identify these changes to the RNAT and spot outbreaks of serious infection that can lead to meningitis,” added Loh.
 
The study used whole-genome sequences from samples freely available from the Meningitis Research Foundation (MRF) Meningococcal Genome Library, developed by Public Health England, the Wellcome Trust Sanger Institute, and the University of Oxford as a project funded by MRF.

Linda Glennie, Director of Research, said: “Our genome library is a world first for meningitis. The data it houses provides the complete genetic blueprint of every sample of meningococcal bacteria from thousands of cases of meningitis or septicaemia in the UK over many years. By comparing these samples, researchers can find clues that will help us defeat the diseases. 
 
“Families affected by meningitis often ask us ‘why me... why my child?’ It is so difficult to for them because we don’t know why the bacteria turns deadly is some cases. This research helps to get us a step closer to providing answers.”
 
The Swedish Foundation for Strategic Research, Knut and Alice Wallenberg Foundation, and Swedish Research Council funded the research.
 
Collaborators on the project included, the National Reference Laboratory for Neisseria meningitidis, Örebro, Sweden and Singapore Centre for Environmental Life Sciences Engineering, Nanyang Technological University, Singapore.
 
Meningitis is a complex disease and further research is needed to strengthen the association between hypercapsulation and the progression of invasive meningococcal disease. To build knowledge in meningitis genomics, MRF is helping to establish a Global Meningitis Genome Partnership - a co-ordinated approach to collecting and sharing global genomic data for the leading causes of bacterial meningitis.


Header image: A coloured SEM picture of Neisseria meningitidis by Hannes Eichner, Francesco Righetti and Edmund Loh.