COVID-19: Discovery of a Molecular Signature of Pediatric Myocarditis

enfant masqué

© Adobe Stock


In very rare cases, children having contracted COVID-19 go on to develop severe inflammation 4 to 6 weeks after infection with SARS-CoV-2. In two-thirds of them, this inflammatory syndrome affects the heart, leading to myocarditis. In a study published in the journal MED, researchers, doctors and teacher-researchers from Inserm, the Paris hospitals group AP-HP and Université de Paris at the Imagine Institute, in collaboration with Institut Pasteur, analyzed blood samples from a cohort of 56 pediatric patients admitted to Hôpital Necker Enfants-Malades AP-HP. What they saw was the abnormal expression of several genes associated with the development of severe forms of myocarditis. A molecular signature that could ultimately help identify those children at risk of developing this rare cardiac inflammation.

Certain children with SARS-CoV-2 develop severe inflammation four to six weeks after infection, with varying symptoms: fever, stomach pain, skin rashes, etc. In around 70% of cases, this so-called “multisystem” inflammatory syndrome affects the myocardium, the muscle responsible for heart contractions. These severe cases of myocarditis were first reported in the UK, in March 2020, before being observed in Italy, France, and then all over the world. What is the explanation behind these rare forms?


Cutting-edge analyses

In a study published in MED – a journal from Cell Press –, conducted by Inserm researchers Frédéric Rieux-Laucat and Mickaël Ménager (*) working in two laboratories at the Imagine Institute (Inserm, Université de Paris, Paris hospitals group AP-HP), in collaboration with doctors from Hôpital Necker-Enfants Malades AP-HP and Institut Pasteur, cutting-edge molecular investigations were conducted in order to find out more. The result of these investigations was the identification of several genes linked to the development of severe forms of myocarditis in these children.

As part of the study, the authors analyzed blood samples from 56 children hospitalized between April 6 and May 30, 2020. A total of 30 had developed multisystem inflammatory syndrome following SARS-CoV-2 infection, 21 of whom with a severe form of myocarditis, and 9 without. “To understand the difference between these two patient groups, we did several analyses using state-of-the-art techniques:  an ultra-sensitive assay of cytokines – the immune system hormones that enable an appropriate response in case of infection –, characterization of blood cell composition, and a cell-by-cell analysis of gene expression“, explains Ménager.


Three molecular abnormalities

In both groups, the researchers found reduced numbers of monocytes and dendritic cells (white blood cells), increased inflammatory cytokine levels, and an overactivation of the so-called “NF-kB pathway” within these cells.

“NF-kB is a molecular pathway that enables a set of genes to be activated, resulting in the production of proteins tasked with orchestrating the immune response,” summarizes Rieux-Laucat. However, it is precisely the overactivation of this system that triggers hyperinflammation in these patients.

Following closer comparison of the dendritic cells and monocytes of the two groups, the authors observed three specific anomalies in patients with myocarditis: lack of inhibition in the NF-kB pathway, overproduction of “TNF-α” (cytokine involved in NF-kB pathway activation), and finally a lack of response to type I and II interferons (cytokines involved in regulating inflammation).

All of these abnormalities can be explained by the abnormal expression of certain genes. In order to identify these genes, the authors carried out a cell-by-cell genetic analysis.

“Like this we were able to identify and validate over one hundred genes overexpressed specifically in the monocytes and dendritic cells of patients with severe forms of myocarditis, explains Ménager. A molecular signature that could ultimately enable the development of tests to identify patients at risk of developing this severe cardiac inflammation.


(*) Frédéric Rieux-Laucat heads up the Immunogenetics of Pediatric Autoimmune Diseases laboratory. Mickaël Ménager heads up the Inflammatory Responses and Transcriptomic Networks in Diseases laboratory and the LabTech Single-Cell@Imagine, a platform dedicated to the cell-by-cell study of gene expression.

A Genetic Cause of Tree Man Syndrome (Skin Papillomavirus) Identified for the First Time


Papillomavirus. © Inserm/U190


Most of us carry human papillomaviruses (HPVs) – particularly skin papillomaviruses that generally cause warts or benign local lesions. However, on very rare occasions worldwide patients develop severe forms of these viral diseases, including “tree man” syndrome. This highly debilitating disease manifests as the uncontrolled growth of horn-like skin lesions for which surgery is ineffective. As part of an international collaboration, researchers from Inserm, teacher-researchers from Université de Paris, and doctors from AP-HP, all grouped at the Imagine Institute (Inserm/Université de Paris, Paris hospitals group AP-HP) located at Necker Hospital for Sick Children AP-HP, have been the first to reveal a genetic cause of tree man syndrome. This research was conducted by Vivien Béziat, under the supervision of Profs. Jean-Laurent Casanova and Laurent Abel, who run a laboratory with branches in Paris and New York’s Rockefeller University1. It was published on July 1, 2021, in the journal Cell.

There are over 200 human papillomaviruses (HPVs), with some causing benign skin lesions such as common or plantar warts, and others with the potential to cause cervical cancer. The Human Genetics of Infectious Diseases laboratory has focused on skin HPVs, working for several years to understand why these usually harmless infections take a severe turn in a few very rare cases.

A genetic mutation increases susceptibility to skin papillomaviruses

In a publication in the journal Cell, the team of Vivien Béziat, Inserm researcher in the Human Genetics of Infectious Diseases laboratory and first author of the publication, studied the genetic characteristics of an Iranian patient with tree man syndrome, and two members of his family presenting with a severe skin HPV infection involving large numbers of warts on their hands and feet, but who had not developed the syndrome. What the three patients were found to have in common was a mutation of the CD28 gene, which usually plays a major role in activating T cells – the immune cells that destroy the cells infected by a virus.

In these patients, the CD28 gene mutation prevents the immune system from recognizing the virus and from mounting an appropriate response. The virus then proliferates in the keratinocytes, the cells that make up the skin’s epidermis, causing the uncontrolled multiplication of skin warts and/or horn-like lesions. This is the first time that a genetic cause of tree man syndrome has been identified.

The CD28 gene, central for resisting certain skin papillomaviruses, but not for the immune system

However, it was when analyzing the CD28 mutation that the researchers made a different discovery. The CD28 gene, until now considered a mainstay in immune system function and T cell response, does not appear to play such a major role. The medical histories of the three patients showed exposure to several HPV types and to a very large number of other pathogens. Yet only the patient with tree man syndrome developed a severe reaction to HPV2, and only the two members of his family did so to HPV4.

“These patients only showed abnormally high susceptibility to certain papillomaviruses of the gamma-HPV and alpha-HPV genus. Based on the work done over the past 30 years, we thought that a CD28 gene dysfunction would actually make patients susceptible to many infectious agents. But even if their immune response is weakened, the patients defend themselves well against other pathogens,explains Béziat.

A discovery which therefore provides new insights into genetic susceptibility to HPVs and challenges the dogmas of T cell-mediated immune response.

“No treatment has so far been shown to be effective against tree man syndrome”. A hematopoietic stem cell transplant to replace the patient’s immune system is being considered. However, this major, costly treatment is not easily accessible to populations living in less developed countries, who will progress towards very severe forms of the disease, notably due to lack of access to care. By advancing research, the team hopes to accelerate access to treatment for these patients.


1 The Human Genetics of Infectious Diseases laboratory is directed by Jean-Laurent Casanova and Laurent Abel and is located at the Imagine Institute in Paris and Rockefeller University in New York. At both branches, Casanova heads up genetics and experimental immunology, whereas Abel heads up genetics and mathematical epidemiology.

Un nouveau traitement en essai clinique chez un premier enfant achondroplase en France


A Major Breakthrough in Understanding the Predisposition of Newborns to Group B Streptococcal Meningitis


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

Food Emulsifiers Increase Pathogenicity of Certain Bacteria and Risk of Intestinal Inflammation

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.

Moreover, in mouse models where the microbiota had been comprised of a low diversity of bacteria, they observed that the animals were protected against the negative effects of certain emulsifiers.

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.

A New Therapeutic Target for Type 2 Diabetes Discovered Thanks to a Rare Disease

An image representing a 3D photo of a human adipocyte: in green the ALMS1 protein reservoir, in red a part of the cytoskeleton, and in blue the cell nucleus. © Vincent Marion

A new therapeutic target for type 2 diabetes has recently been identified by researchers from Inserm and Université de Strasbourg, in collaboration with several European hospitals. The target in question is ALMS1, a protein whose function is still poorly understood. It has come to light thanks to the study of a rare disease, Alström syndrome, which affects different organs and associates childhood obesity and type 2 diabetes. This research paves the way for the development of a new drug and has been published in Diabetes.

Obesity and type 2 diabetes are strongly intertwined. Around 80% of obese subjects develop the disease, although the reasons for this association have not yet been clearly established. In order to study the links between them, the team of Inserm researcher Vincent Marion at the Laboratory of Medical Genetics (Inserm/Université de Strasbourg) focused on Alström syndrome, an extremely rare monogenic[1] disease that affects multiple organs, and leads to both obesity and type 2 diabetes.

This disease is caused by mutations in the ALMS1 gene coding for a protein whose function is still poorly understood. “The fact that it is a monogenic disease provided a starting point for studying the complex mechanisms of type 2 diabetes,” emphasizes Marion. The team found that abnormalities in adipose tissue caused by loss of ALMS1 function led to type 2 diabetes in people with Alström syndrome. What is more, in animals, restoring the function of this protein restored blood glucose balance. The researchers have therefore identified a new therapeutic target for type 2 diabetes: the ALMS1 protein.

These findings are the result of several years of research based on different clinical and experimental approaches, carried out in vivo in subjects with Alström syndrome and in a mouse model for the disease, as well as on in vitro observations. The researchers have identified abnormalities in the structure and function of adipose tissue in people with Alström syndrome that are far more significant than those found in obese individuals with the same body mass but without the disease. In mice, these abnormalities were associated with the inability of adipocytes, which make up the adipose tissue, to absorb glucose. “By preventing adipocytes from absorbing glucose, the loss of ALMS1 function is directly responsible for type 2 diabetes, making it a very interesting therapeutic target,” explains Marion.

ALMS1 therapeutic target in diabetes

In the study published in Diabetes, the researchers wanted to evaluate the therapeutic relevance of this protein by restoring the expression of the ALMS1 gene in their mouse model. Doing so restored blood glucose balance in these animals by increasing their glucose absorption.

The researchers also worked in vitro with adipocytes from people with Alström syndrome in order to understand the underlying molecular mechanisms that explain why this protein helps restore blood glucose balance. They found that in these adipose tissue cells, the ALMS1 protein acts far downstream of an insulin-controlled molecular signal chain.

“Thanks to this research using a rare disease model, we have discovered a molecule that by itself is capable of increasing glucose absorption by the adipocytes and maintaining good blood glucose balance. This makes it a very good therapeutic target for type 2 diabetes in general, whether or not it is associated with obesity,” explains Marion.

By identifying and using a molecule capable of targeting this ALMS1 protein in subjects with type 2 diabetes, the hope is to improve diabetes control, regardless of the level of circulating insulin in these individuals. A peptide is already under development.

Preclinical animal testing is being finalized and clinical trials are expected to begin in 2021 in subjects with type 2 diabetes, whether or not they are obese. Ultimately, if this drug candidate proves to be safe and effective, it could be prescribed alone or in combination with other diabetes drugs that target other molecular mechanisms.

On the strength of these results, the researcher has founded the company ALMS Therapeutics, in order to capitalize on this discovery.

[1] Genetic disease resulting from the mutation of a single gene

The Placenta Could Retain a Memory of Tobacco Exposure Prior to Pregnancy

©fotografierende on Unsplash

It is well-known that giving up smoking before pregnancy considerably reduces the health risks for both mother and child. Research by a team from Inserm, CNRS and Université Grenoble Alpes at the Institute for Advanced Biosciences, published in BMC Medicine, took a closer look at the subject showing for the first time that tobacco consumption, even when stopped before pregnancy, can have an impact on the placenta. By studying the placental DNA of 568 women, the team has shown that smoking not just during but also before pregnancy leads to epigenetic modifications (DNA methylation) which could have consequences on its course.

Although it has been shown that tobacco consumption during pregnancy has many negative health impacts for both mother and child, the mechanisms involved are still poorly understood. Previous studies have linked tobacco consumption during pregnancy to alterations in DNA methylation – a form of epigenetic modification (see boxed text) involved in gene expression – in umbilical cord blood and the cells of the placenta. Indeed, while the placenta plays a crucial role in the development of the fetus, it is vulnerable to many chemical compounds.

However, what had not been studied up until now was the impact on placental DNA methylation of tobacco exposure prior to pregnancy.

A team from Inserm, CNRS and Université Grenoble Alpes at the Institute for Advanced Biosciences measured and compared the impact of tobacco consumption on placental DNA methylation in pregnant women in the three months preceding pregnancy and/or during pregnancy.

The researchers studied DNA from samples of placenta collected at the time of delivery from 568 women of the EDEN1 cohort, who were divided into three categories: non-smokers (who had not smoked in the three months prior to pregnancy or during it), former smokers (who had given up smoking in the three months prior to pregnancy) and smokers (who had smoked both throughout pregnancy and in the three months prior to it).

In the smokers, the scientists observed that 178 regions of the placental genome showed alterations in DNA methylation. In the former smokers, they identified that DNA methylation was still altered in 26 of these 178 regions. Only in the women having smoked during pregnancy was methylation altered in the remaining 152 regions.

The regions that were altered most often corresponded to so-called enhancer zones, which remotely control the activation or repression of genes. In addition, some of them were located on genes known to play an important role in fetal development.

While many regions appear to have a normal methylation profile in women after they have stopped smoking, the presence of some DNA methylation changes in the placenta of those having stopped before pregnancy suggests the existence of an epigenetic memory of tobacco exposure,” says Inserm researcher Johanna Lepeule, who led this work. She suggests that changes in placental DNA methylation at the level of the genes related to fetal development and enhancer regions may partly explain the effects of smoking observed on the fetus and the subsequent health of the child.

The next steps in this research are aimed at determining whether these alterations impact the mechanisms involved in fetal development and whether they may have consequences for the health of the child.


[1] The pregnant women were recruited between 2003 and 2006 in the university hospitals of Nancy and Poitiers.


Learn more about epigenetic modifications and DNA methylation

Epigenetic modifications are materialized by biochemical marks present on DNA. Reversible, they do not lead to changes in DNA sequence but do induce changes in gene expression.  They are induced by the wider environment: the cell receives signals informing it about its environment, and specializes itself accordingly, or adjusts its activity. The best characterized epigenetic markers are DNA methylations, involved in the control of gene expression.

A Novel Genome Editing Tool for Rare Hereditary Diseases

Researchers have developed a tool to modify the genome of stem cells and restore the production of therapeutic proteins in patients. © Adobe Stock

Finding appropriate treatments for patients with hereditary diseases, such as hemophilia and most metabolic disorders, is often a challenge for researchers. Targeted genome editing, particularly via the CRISPR-Cas9 technique, has opened up some interesting avenues in recent years. Researchers from Inserm, Université d’Evry, Université Paris-Saclay and Genethon have developed a novel platform for modifying the genome of hematopoietic stem cells, which give rise to blood cells. The use of these tools could provide new therapeutic solutions for many patients with rare genetic diseases. The results of this research have been published in Nature Communications.

Various hereditary diseases, such as hemophilia or most metabolic disorders, are characterized by the absence of certain proteins in the body. Hemophilia in particular is caused by a clotting factor deficiency. In the event of injury, the blood does not clot properly, resulting in severe bleeding in some cases. In metabolic disorders, the cause is a metabolic enzyme deficiency that impedes the degradation of certain substrates, leading to vital organ failure and even death.

Although substitution treatments exist, they can be burdensome for patients and particularly costly. What is more, because they involve bringing foreign proteins into the body, these treatments can be neutralized by the immune system.

To explore new therapeutic solutions, a team from the Integrated Genetic Approaches in Therapeutic Discovery for Rare Diseases laboratory (Inserm/Université d’Evry/Université Paris-Saclay) led by Mario Amendola, an Inserm researcher at Genethon, has focused on two rare hereditary diseases: hemophilia B and a metabolic condition called Wolman disease.

The first concerns around one in 25,000 boys and is caused by a deficiency of a clotting protein called factor IX. The second affects one in 100,000 births and is caused by a lysosomal acid lipase (LAL) deficiency.

Restoring the production of therapeutic proteins

The researchers have developed a novel genome-editing platform aimed at restoring the secretion of these proteins. Described for the first time in the journal Nature Communications, this unique tool is based on the editing of the hematopoietic stem cell genome. Hematopoietic stem cells give rise to the various blood cell types, differentiating in particular to form red blood cells.

To achieve this result, the researchers first identified and characterized a region of the hematopoietic stem cell genome that could be safely modified. Using “CRISPR-Case 9” genetic scissors, they inserted isolated DNA sequences into it so that only the red blood cells derived from it could then systematically express a large amount of factor IX or LAL.

“This study aims to describe for the first time a technique for modifying the genome of hematopoietic stem cells. This is so that red blood cells, which are very abundant in the body, then secrete beneficial therapeutic proteins – without risk to patients and without rejection by the immune system, since they are produced by their cells,” clarifies Amendola.

This research therefore opens up interesting therapeutic avenues for many patients, requiring testing of the platform in a clinical setting. “The technology is promising and applicable to many diseases, but to make it a therapeutic solution in its own right, it is essential to continue this fundamental work in order to bring it to the hospital, to the patients,” concludes Amendola.

Type 1 Interferon Deficiency: A Blood based Signature for Detecting Patients at Risk of Severe Covid-19

Image de microscopie du Coronavirus SARS-CoV-2 responsables de la maladie COVID-19 accrochés aux cellules épithéliales respiratoires humaines

SARS-Cov-2 coronavirus responsible for COVID-19 disease attached to human respiratory epithelial cells ©M.Rosa-Calatraval/O.Terrier/A.Pizzorno/E.Errazuriz-cerda


Paris, July 16th – Which patients will develop a severe form of Covid-19? This is a key question that needs to be answered to improve the individual management and prognosis of patients. In a study published in Science on July 13, teams from AP-HP, Inserm, Université of Paris, Institut Pasteur and Institut Imagine describe a unique and unexpected immunological phenotype in severe and critical patients, consisting of a severely impaired response of interferon (IFN) type I, associated with a persistent blood viral load and an excessive inflammatory response. These data suggest that IFN type I deficiency in the blood could be a hallmark of severe forms of Covid-19. It also supports the potential value of therapeutic approaches that combine early administration of IFN, with appropriate anti-inflammatory therapy targeting IL-6 or TNF-α, in patients preventing severe disease forms.

Approximately 5% of people with Covid-19 progress to a severe or critical form, including the development of severe pneumonia that progresses to acute respiratory distress syndrome. While these forms sometimes occur early in the course of the disease, clinical observations generally describe a two-stage progression of the disease, beginning with a mild to moderate form, followed by respiratory aggravation 9 to 12 days after the onset of the first symptoms. This sudden progression suggests deregulation of the host inflammatory response. A growing number of indications suggest that this aggravation is caused by a large increase in cytokines. This runaway inflammatory response is correlated with massive infiltration in the lungs of innate immune cells, namely neutrophils and monocytes, creating lung damage and acute respiratory distress syndrome.

By analogy with a genetic disease leading to a similar pulmonary pathology identified at Institut Imagine by the team of Inserm researcher Frédéric Rieux-Laucat, the initial hypothesis assumed excessive production of interferon (IFN) type I, a marker of the response to infections. However, in seriously ill patients, the teams of Darragh Duffy (Dendritic Cell Immunobiology Unit, Institut Pasteur/Inserm), Frédéric Rieux-Laucat (Laboratory of Immunogenetics of Pediatric Autoimmune Diseases at Institut Imagine – Inserm/Université de Paris), Solen Kernéis (Mobile Infectiology Team, AP-HP. Centre – Université of Paris) and Benjamin Terrier (Department of Internal Medicine, AP-HP. Centre – Université of Paris) show that the production and activity of type-I IFN are strongly reduced in the most severe forms of Covid-19.

In addition, there is a persistent blood viral load, indicating poor control of viral replication by the patient’s immune system which leads to an ineffective and pathological inflammatory response.

The inflammation, caused by the transcription factor NF-kB, also leads to increased production and signaling of tumor necrosis factor (TNF)-alpha and the pro-inflammatory cytokine interleukin IL-6.

Distinct type-I IFN responses may be characteristic of each stage of the disease

This low signature of type-I IFN differs from the response induced by other respiratory viruses such as human respiratory syncitial virus or influenza A virus, both of which are characterized by high production of type-I IFN.

The study also showed that low levels of type-I IFN in plasma precede clinical worsening and transfer to intensive care. Levels of circulating Type 1 IFN could even characterize each stage of disease, with the lowest levels observed in the most severe patients. These results suggest that in SARS-CoV-2 infection, the production of type-I IFN is inhibited in the infected host, which could explain the more frequent severe forms in individuals with low production of this cytokine, such as the elderly or those with co-morbidities.

Therefore, type-I IFN deficiency could be a signature of severe forms of COVID-19 and could identify a high-risk population.

These results further suggest that the administration of IFN-alpha/Beta combined with anti-inflammatory therapy targeting IL-6 or TNF-α, or corticosteroids such as dexamethasone, in the most severe patients could be a therapeutic avenue to be evaluated for severe forms of COVID-19.

Blood Stem Cell Immune Memory: A New Research Avenue in COVID-19

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.

The team’s discoveries could elucidate the molecular mechanisms at play in this protection and open up new avenues for vaccines – particularly 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.