Every year throughout the world, Group B Streptococcal (GBS) meningitis affects thousands of newborns. Often fatal, the disease can also lead to severe after-effects in survivors. However, in adults, GBS is an uncommon cause of meningitis. Researchers from Inserm, Collège de France, CNRS, Institut Pasteur, Université de Paris and Paris hospitals AP-HP have now provided elements to explain the predisposition of newborns to GBS meningitis. They have identified and demonstrated that receptors for a bacterial protein enabling penetration of the blood-brain barrier[1] are overexpressed in newborns and absent in adults. The results of their research have been published in Journal of Clinical Investigation.

Group B Streptococcus (GBS) is present in the vaginal microbiota of 20-30% of women. To avoid infecting the baby during labor – which could lead to septicemia and, in the severest cases, meningitis – many developed countries, including France, perform vaginal screening a few weeks before birth. Women found to carry GBS are then given antibiotics during labor.

While this strategy has led to a strong reduction in the incidence of GBS infections during the first week of life, it has had no effect on those occurring between 1 week and 3 months of life.

What is more, many countries offer no such prenatal screening and large numbers of newborns die of GBS meningitis. It is therefore a major public health problem.

Predisposition of newborns

In order to better understand the disease and improve the care of mothers and children, Inserm researcher Julie Guignot and her team at Institut Cochin (Inserm/CNRS/Université de Paris)[2] sought to understand what predisposes newborns to this type of meningitis that affects children and adults only in exceptional cases.

In previous research, the scientists had shown that a variant of GBS was responsible for over 80% of meningitis cases in newborns. This variant expresses specific proteins on its surface, which play an essential role in crossing the blood-brain barrier that separates the blood from the brain.

Using complementary approaches, the researchers demonstrated that one of the proteins exclusively expressed by this variant specifically recognized two receptors present in the cerebral blood vessels that constitute the main element of the blood-brain barrier. Thanks to human samples, they have shown that these receptors are overexpressed in newborns. However, these brain receptors are not present in adults, which explains why GBS is only very rarely responsible for meningitis beyond the first year of life, given that the bacteria cannot reach the brain.

Using animal models of meningitis, the researchers confirmed their findings, showing that the expression of these receptors during the postnatal period contributed to the susceptibility of newborns to meningitis caused by the GBS variant.

For the researchers, these findings open up interesting therapeutic research avenues, particularly in regard to meningitis treatments. “The idea would be to develop treatments to target these receptors in the blood-brain barrier. In the longer term, we would like to study the individual factors of susceptibility leading to the development of these infections. This would make it possible to perform personalized monitoring of at-risk infants born to mothers colonized by this variant,” explains Guignot.

[1] Physiological barrier between the blood and the brain that protects the latter from toxic substances and pathogenic microorganisms

[2]The Structural Molecular Biology and Infectious Processes laboratory (CNRS/Institut Pasteur), the Center for Interdisciplinary Research in Biology, (CNRS/Collège de France/Inserm), the Institute for Advanced Biosciences (CNRS/Inserm/UGA), among others, also participated in this research

Certain bacteria of the intestinal microbiota (shown in red) are able to penetrate the normally sterile mucus layer (shown in green). © Benoit Chassaing

Diet is believed to play a role in triggering intestinal inflammation that can lead to the development of certain conditions, such as Crohn’s disease. Researchers from Inserm, CNRS and Université de Paris have shown that the emulsifiers present in many processed foods could have a harmful impact on specific bacteria in the gut microbiota, leading to chronic inflammation. Their findings have been published in Cell Reports.

The prevalence of chronic inflammatory bowel disease is increasing in all countries of the world and is thought to affect nearly 20 million people. Characterized by inflammation of the wall of part of the digestive tract, these conditions include Crohn’s disease and ulcerative colitis.

Several factors, both genetic and environmental, have been implicated in explaining the intestinal inflammation associated with these diseases. For several years, Inserm researcher Benoît Chassaing and his team at Institut Cochin (Inserm/CNRS/Université de Paris) have studied the role of diet, particularly the impact of certain additives such as emulsifiers.

Widely used by the food industry in many processed products, the purpose of emulsifiers[1] is to improve texture and extend shelf life. For example, lecithin and polysorbates ensure the smooth texture of mass-produced ice cream and prevent it from melting too quickly once served.

In previous studies based on animal models, the researchers had already shown that the consumption of dietary emulsifiers negatively alters the microbiota in such a way as to promote inflammation.

This led to their hypothesis that the emulsifiers would impact only specific bacteria, which are harmless under “normal” conditions but have the potential to cause disease. It is only in the presence of emulsifiers that these bacteria would be able to promote the development of chronic intestinal inflammation and its associated diseases.

E. coli as a model

As part of their study published in Cell Reports, the researchers used two mouse models: one without a microbiota and the other with a simple microbiota containing only eight species of bacteria. They colonized them with a strain of Escherichia coli (“AIEC bacteria”) associated with Crohn’s disease.

The researchers were interested in the effects of two emulsifiers administered following the colonization of the mice by the AIEC bacteria. Although the consumption of the emulsifiers had no harmful effects on the animals in the absence of these bacteria, they observed the development of chronic intestinal inflammation and metabolic deregulation when they were present. The presence of both the AIEC bacteria and the emulsifier was necessary and sufficient to induce chronic intestinal inflammation.

Further analysis revealed that when these bacteria were in contact with the emulsifiers, they over-expressed groups of genes that increased their virulence and propensity to induce inflammation. “We were able to identify a mechanism by which dietary emulsifiers can promote chronic intestinal inflammation in people who harbor certain bacteria, such as AIEC bacteria, in their digestive tract,” says Benoît Chassaing , who coordinated the study.

The next step is to list all the bacteria that have the same effects in contact with these food additives.

In the longer term, studies to identify and stratify patients according to the composition of their microbiota and risk of inflammation could be set up with the aims of taking a preventive approach and implementing personalized nutritional recommendations. People with specific microbiotas, sensitive to emulsifiers, could benefit from such recommendations.

“And while it is illusory to think that we can banish emulsifiers from our diet, the models and methodologies we have developed here will also allow us to test the action of several types of emulsifiers on the microbiota in order to identify those without harmful effects, and thus encourage their use,” concludes Chassaing.

[1] An emulsifier is a compound that has an affinity for both water and oil and allows the different phases of a compound to remain mixed together.

Immune cells seen by fluorescence microscopy. Blood immune cells store information from past infections and then produce more immune cells like the macrophages captured in this image.© Sieweke lab/CIML.

Blood stem cells have a surprising ability. In addition to ensuring the continuous renewal of blood cells, they keep track of past infections so that faster and more effective immune responses can be triggered in the future. This is according to a new study co-led by Inserm researcher Sandrine Sarrazin and CNRS researcher Michael Sieweke at the Center of Immunology Marseille-Luminy (CNRS/Inserm/Aix-Marseille Université, France) and the Center for Regenerative Therapies Dresden (Germany). This discovery could have a significant impact on future vaccination strategies, particularly those being explored for COVID-19, and also further research into new treatments that modulate the immune system. These findings have been published in Cell Stem Cell.

It has long been known that the adaptive immune system has a memory. Following exposure to an infectious pathogen, lymphocytes in the blood become specific to it, with some of them remaining in the body long-term. The principles of vaccination are based on the knowledge of these immune mechanisms.

More recent studies suggest that the innate immune system, which enables immediate defense of the body in response to an infection, also has a form of memory. For example, researchers have shown that the innate immune system continues to be more efficient in the event of reinfection despite the very short lifespan of the immune cells, such as monocytes or granulocytes. They went on to suspect that this innate immune system memory is in fact inscribed in the blood stem cells, which have a very long lifespan and are at the origin of various mature immune cells.

To verify this hypothesis, scientists at the Center of Immunology Marseille-Luminy (CNRS/Inserm/Aix-Marseille Université) and the Center for Regenerative Therapies Dresden (Germany) carried out research whose findings have been

published in Cell Stem Cell. The researchers began by exposing mice to a molecule found on the surface of the E. coli bacterium (lipopolysaccharide or LPS), a pathogen which is commonly used in laboratories to mimic infections.

They then transferred blood stem cells taken from these animals to non-infected mice whose immune systems had previously been destroyed. The aim was to fully reconstitute their immune systems based on these stem cells.

The researchers then infected mice from this group with a live bacterium of the species P. aeruginosa, observing a mortality rate of just 25%. However, in the control mice whose stem cells had never been exposed to a pathogen, this rate was 75%. 

“This research strongly demonstrates that the blood stem cells have a memory function that we did not know existed. Initial exposure to a pathogen makes them better equipped to face subsequent infections”, explains Sandrine Sarrazin.

This mechanism is not specific to pathogens because, in another experiment, an initial exposure of the blood stem cells to a viral antigen protected the mice from secondary exposure to P. aeruginosa. The scientists made the surprising discovery that the protection afforded by this immune system memory extends beyond the infectious agent used for the first infection.

The researchers then looked at how this memory is coded. When studying the genome of the blood stem cells of the infected mice, they observed lasting modifications in its spatial organization. Changes that are likely to modify the expression of some genes implicated in the innate immune response. “At the time of first contact with the pathogen, genes required for the immune response are in fact put forward long-term so as to rapidly activate the immune system in the event of a second infection”, explains Bérengère de Laval, lead author of the study. Finally, the team looked for molecules implicated in this change of genome structure and discovered that the protein C/EBP beta played a major role.

Research relevant in fighting COVID-19?

These results are particularly relevant during this period of SARS-Cov-2 coronavirus pandemic.

Recent findings suggest that the BCG vaccine – it too known for inducing innate immune memory – also acts at blood stem cell level and offers a certain degree of protection from respiratory infections. Studies are ongoing in order to test its utility against COVID-19.

“Our discoveries represent a major contribution to understanding immune system memory and blood stem cell functions. They also point towards new strategies for stimulating or limiting immune response in various disease states and could make it possible to refine current vaccination strategies for better protection from various pathogens, including SARS-CoV-2″, hopes Michael Sieweke.