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Category: Immunology, inflammation, infectiology and microbiology

Good tolerance of the BNT162b2 vaccine (Pfizer / BioNTech) and good efficacy of the immune response against SARS-CoV-2 variants in patients with systemic lupus

Posted on by Graziella Cara

vaccin anti covid

Covid vaccine © Adobe Stock

 

Teams from the immunology department and internal medicine department 2 of the Pitié-Salpêtrière AP-HP hospital, Sorbonne University and Inserm, measured the antibody and cellular responses generated by a messenger RNA vaccine in patients with systemic lupus (LS). This work, coordinated by Professors Guy Gorochov (CIMI-Paris) and Zahir Amoura (National Lupus Reference Center) shows that vaccination is both well tolerated and effective, even against worrying variants. For the first time, the factors associated with a poor vaccine response in some of these patients have been identified in order to better anticipate who should benefit from reinforced protective measures and / or adapted vaccine protocols. This work was the subjectfrom an October 4 publication in the journal Annals of Rheumatic Diseases.

Systemic lupus (LS) is a chronic autoimmune disease preferentially affecting young women. The attacks are mainly articular, cutaneous, renal, cardio-respiratory, neurological and hematological. The disease is characterized by the production of autoantibodies directed against nuclear antigens. It typically evolves in spurts. For these patients, two hypotheses were considered concerning the effects of the messenger RNA vaccination: the occurrence of more frequent adverse effects, or even the exacerbation of the disease in patients with LS, or an ineffective response to vaccination for patients with LS. patients on immunosuppressants.

The teams compared the effects of vaccination in 136 patients with systemic lupus (LS). 126 of them, who received 2 doses of the BNT162b2 vaccine (Pfizer / BioNTech) and followed the entire clinical-biological surveillance course, were included in the final analysis. The two vaccine doses were separated by 21 to 28 days with a clinical-biological evaluation from the day of the first injection and up to 42 days after it (D42). The clinical activity of the disease was measured at each visit (D0, D7-14, D21-28, D42) using standardized indices. Some patients were vaccinated while their lupus disease was active.

During the 40-day follow-up, no significant change in disease activity was observed, either in patients active at the time of vaccination, or in those who showed no signs of the disease. The only notable side effects related to the vaccination were mild or moderate pain at the injection site.

A pseudo virus expressing the envelope (Spike) of the reference SARS-CoV-2 (D614G) or that of the variants B.1.1.7 (Alpha), B.1.617.1 (Kappa), B.1.617.2 (Delta ), B.1.617.3, B.1.1.28 (Gamma) and B.1.351 (Beta) was used to measure the neutralizing activity of the serum collected on D42. 82% of the patients tested were able to effectively neutralize the reference strain and the Alpha variant. As expected, a slight decrease in the neutralization efficiency of the other variants was noted, mainly for the Beta variant, neutralized by the serum of 60% of the patients tested, while the Delta variant was neutralized in 76% of cases.

At present, the vaccine response criteria are still poorly understood. Among the various treatments received against lupus, this work was able to combine methotrexate and mycophenolate mofetil, two immunosuppressive treatments, with lower rates of IgG responses to the human receptor binding domain (RBD) of SARS-CoV-2. (independently of immunosuppressive treatments). Long-term corticosteroid intake (median prednisone dose: 19 mg / day) was not, however, associated with a poor vaccine response.

This work evaluated certain therapeutic and biological criteria of vaccine response.

A decreased vaccine response, i.e. a lower level of protective antibodies, has been shown when the patient with LS is treated with methotrexate or mycophenolate mofetil (two immunosuppressive treatments). Conversely, taking corticosteroids, regularly prescribed in LS, was not associated with a poor vaccine response.

The study also looked at the immune status of patients at the start of the vaccination protocol. The level of circulating naive B lymphocytes (CD19 + CD27-IgD +) and the overall concentration of IgG antibodies on D0 were associated with a more intense vaccine response.

In conclusion, the vaccination of lupus patients with BNT162b2 is very well tolerated and its efficacy is reduced only in patients treated with methotrexate or mycophenolate mofetil. A pre-existing alteration in the adaptive humoral response is also associated with the poor vaccine response.

Covid-19 : identification de cellules immunitaires associées à la survie dans les formes sévères de la maladie

Posted on by Léa Surugue

lymphocyte immunité

The cellular immune response is based on the T cells recognizing cells that have been infected with the virus. © Adobe stock

 

A better understanding of the precise mechanisms of immune response to SARS-CoV-2 is essential if we are to improve patient care and continue to develop effective new vaccines. Since the pandemic began, many studies have tried to explain what differentiates the immune response of people with severe forms of COVID-19 resulting in death from that of other patients. In a new study, researchers from Inserm and Sorbonne Université at the Center for Immunology and Infectious Diseases, in collaboration with physician researchers from Paris hospitals group AP-HP, focused on a type of immune response known as the cellular immune response. They show that certain cells involved in this response, CD8+ T cells, are present in smaller quantities in patients who have died from COVID-19. Some of them are considered to constitute predictive markers of survival. This research has been published in JCI Insight.

Since the COVID-19 pandemic began, the immune response triggered following SARS-CoV-2 infection has been the subject of much research. At a time when the Delta variant has spread across the world, understanding the precise mechanisms of the adaptive 1 immune response to the virus appears essential if we are to continue to develop effective vaccines that are less sensitive to the emergence of new variants.

In the majority of cases, infection with SARS-CoV-2 only results in relatively mild symptoms (or even forms that are asymptomatic). However, in some cases, serious forms develop, associated with severe, life-threatening symptoms that sometimes require intensive care.

Numerous publications have already shown that different profiles of immune responses are associated with the severity of symptoms. However, we still do not have enough data to understand the role of the humoral and cellular responses that constitute the adaptive immune response (see box), as well as their involvement in the survival or death of patients with the severest symptoms.

In their study, the scientists from Inserm, Sorbonne Université and Paris hospitals group AP-HP looked at the immune response profiles of 56 patients hospitalized in intensive care, a third of whom died from COVID-19, paying particular attention to the cellular responses, mediated by T cells.

Different types of immune response

There are two broad categories of adaptive immune response: humoral responses, based on the production of antibodies that recognize the virus and can prevent it from infecting its target cells; and cellular responses, based on the T cells recognizing cells that have been infected with the virus. These T cells, through various mechanisms, contribute to the destruction of cells infected with the virus in order to control the viral infection and help eliminate the virus from the body. For this study, the researchers focused on the cellular response.

T cells are a population of heterogeneous cells that can be divided into different subpopulations according to their phenotype (the molecules they express on their surface) and their function (destruction of infected cells, production of molecular messengers, support and activation of other cells…). There are two main types of T cells: CD4+ cells that support the production of antibodies and CD8+ cells, specialized in the destruction of infected cells through the production of cytotoxic molecules.

Numerous publications over the past decades have shown the essential role of cellular responses, in particular that of “cytotoxic effector CD8 cells” (CD8+) in the context of viral infections such as influenza in the elderly or HIV.

Markers of survival

In the study, the team saw significant differences in the amounts of certain T cell subpopulations, between those individuals who survived and those who died from COVID-19.

First, the researchers saw a marked loss of CD8+ T cells capable of recognizing the SARS-CoV-2 nucleocapsid in deceased individuals, compared to individuals who survived the infection. Nucleocapsid is an internal molecule of the virus, highly immunogenic (i.e. capable of inducing an immune response) and well preserved from one SARS-CoV-2 variant to another.

In addition, the individuals who died from COVID-19 had a very low proportion of CD8+ T cells expressing two molecules on their surface (PDL1 and CXCR3), compared to those who survived. Having CD8+ T cells that present PDL1 and CXCR3 could therefore be a molecular signature predictive of survival.

“We have shown that the simple combination of the level of nucleocapsid-specific CD8 T cells and the overall level of CD8+ T cells expressing CXCR3 and PDL1 could predict the survival or death of critical COVID-

19 patients with over 90% accuracy. Both factors are significantly important given the other factors that are potentially important when it comes to severity, such as age and obesity, and more accurately predict the risk of death in patients with severe forms”, emphasizes Inserm researcher Béhazine Combadière, who coordinated the study.

These findings also have important implications for the development of future vaccines. Vaccines capable of targeting nucleocapsid – a highly preserved protein common to the coronaviruses – and of producing a high level of CD8+ T cells specific against this molecule could be useful in preventive vaccination and probably also in therapeutic vaccination in order to promote the survival of patients with severe forms, regardless of which variant they were infected with.

For the team, the next step is to work with people who have already been vaccinated, to see if they produce the immune cells that were predictive of survival in the patients studied in this research.

 

1 Innate immunity is an immediate response that occurs in any individual in the absence of prior immunization. It is the first barrier of defense against various pathogens and mainly brings into play pre-formed (natural) antibodies and lymphocytes that do not present receptors specific to the antigen. Adaptive immunity is established a few days after contact with the pathogen and is the body’s second line of defense. Unlike innate immunity, adaptive immunity is specific for a given antigen.

Neonatal meningitis: the immaturity of microbiota and epithelial barriers implicated

Posted on by Graziella Cara

méningites

© Choroid plexus of mouse neonates. Blue: cell nuclei, green: phalloidin-actin, red: fluorochrome. Credits: Biology of Infection Unit, Institut Pasteur

Meningitis is associated with high mortality and frequently causes severe sequelae. Newborn infants are particularly susceptible to this type of infection; they develop meningitis 30 times more often than the general population. Group B streptococcus (GBS) bacteria are the most common cause of neonatal meningitis, but they are rarely responsible for disease in adults. Scientists from the Institut Pasteur, in collaboration with Inserm, Université de Paris and Necker-Enfants Malades Hospital (AP-HP), set out to explain neonatal susceptibility to GBS meningitis. In a mouse model, they demonstrated that the immaturity of both the gut microbiota and epithelial barriers such as the gut and choroid plexus play a role in the susceptibility of newborn infants to bacterial meningitis caused by GBS. The findings were published in the journal Cell Reports on June 29, 2021.
 

Newborn infants are more likely to develop bacterial meningitis than children and adults. Group B streptococcus (GBS) is the pathogen responsible for a significant proportion of cases of neonatal meningitis. In most instances, infection is preceded by bacterial colonization of the gut. The commensal bacterial gut flora (known as the microbiota) plays a key physiological role, as it is involved in digestion, offers protection from gut pathogens and contributes to tissue differentiation and immune development. Newborns have no gut microbiota; it gradually develops in the first few weeks after birth.

In a new study, scientists from the Institut Pasteur, in collaboration with Inserm, Université de Paris and Necker-Enfants malades Hospital (AP-HP), demonstrated in a mouse model that the immaturity of the gut microbiota in neonates is involved in neonatal susceptibility to meningitis caused by GBS. In the absence of a mature microbiota, the bacteria can extensively colonize the gut. In the absence of a mature microbiota, the barrier function of blood vessels in the gut that the bacteria must cross to reach the brain through the bloodstream is also less effective, and the immune system is unable to control infection.

Unexpectedly, the scientists also demonstrated that, independently of the microbiota, the epithelial barriers formed by the gut and the choroid plexus (the interface between the blood and the cerebrospinal fluid that irrigates the brain) are not entirely mature in newborns, which facilitates bacterial access to the brain.

The signaling pathway known as the Wnt pathway, which is involved in tissue growth and differentiation, is more active in newborns, resulting in a less effective barrier function at the gut and choroid plexus levels in neonates.

“In this study, we show how two factors associated with infancy – the immaturity of the gut microbiota and the growth of gut and choroidal epithelial tissues – play a role in the susceptibility of newborn infants to meningitis caused by GBS, at all stages of infection from gut colonization to dissemination in the brain,” explains Marc Lecuit (university professor/hospital practitioner, Université de Paris and Necker-Enfants Malades Hospital), head of the Biology of Infection Unit at the Institut Pasteur and Inserm and last author of the study.

The results of this research illustrate the importance of the microbiota and its critical role in protecting against infection.

Hippurate, a metabolite derived from gut bacteria, is associated with microbiotal diversity

Posted on by Léa Surugue

Microbiote

Insulin is produced by the beta cells of the pancreatic islets of Langerhans. Cells which, in type 1 diabetes, are destroyed by the immune system. In this study, the administration of hippurate improved blood glucose control and stimulated insulin secretion in animal models. © Inserm/U845/UMRS975/EndoCells SARL

 

Good gut microbiota function has an impact on our general physical and psychological health. Understanding how the architecture of the microbiota and the function of the bacteria that inhabit it affect the body has become a key research focus in recent years.

Within this context, researchers from Inserm and Université de Paris, in collaboration with teams from INRAE, Imperial College London and the University of Copenhagen in Denmark, have shown that hippurate, a metabolite derived from gut bacteria, is associated with microbiotal diversity. Hippurate is thought to play an important role in our cardiovascular and metabolic health, particularly by helping to regulate blood sugar. This research has been published in Gut.

For several years, the gut microbiota has been considered to play a key role in our health. Many scientific studies have highlighted the existence of a link between the diversity of the bacterial strains present and certain health parameters, particularly cardiovascular and metabolic.

The team led by Inserm researcher Dominique Gauguier focused on hippurate, a metabolite produced by the gut bacteria and that is found in urine.

The scientists combined two methods, DNA sequencing (analysis of the genetic profile) of the gut microbiota bacteria and urinary metabolomic profiling (analysis of small metabolites present in urine) in 271 individuals from a Danish cohort (the MetaHIT study).

From the data obtained, the scientists show that high levels of hippurate in urine are associated with greater gut flora diversity and increased microbiotal gene richness, two parameters that protect against cardiometabolic risk (the risk of developing cardiovascular disease and/or diabetes).

The researchers also had information about the participants’ dietary habits and body mass index (BMI). They found that in obese individuals with a diet high in saturated fat and a risk of developing cardiovascular and metabolic problems, high levels of hippurate had beneficial effects on weight and metabolic health.

schéma Gauguier eng

Figure representing the main study findings.

These findings were supplemented by a validation study in obese mice fed a fatty diet. In these animal models, the administration of hippurate improved blood glucose control and stimulated insulin secretion. “This research confirms the importance in human health of gut flora architecture and function by demonstrating the beneficial role of a metabolite produced by gut bacteria. Something we had already shown with the metabolite cresol,” emphasizes Gauguier.

The relevance of these findings is both diagnostic, as hippurate can be considered a biomarker of microbiotal diversity, and therapeutic.

One could, for example, envisage modifying the microbiota using probiotic systems to produce larger quantities of the gut bacteria that synthesize the precursors of hippurate. This would then increase hippurate levels with their attendant protective effects on cardiometabolic risk.

For the scientists, the next step is to continue their research by studying the cellular mechanisms that explain how hippurate promotes insulin secretion and blood glucose regulation.

A personalized precision medicine approach is needed to treat Covid-19 as more than one type of “Cytokine storm” is induced by SARS-CoV-2

Posted on by Graziella Cara

SARS-CoV-2

Electron microscopy of a cell infected with SARS-CoV-2 © Philippe Roingeard, Anne Bull-Maurer, Sonia Georgeault, unité Inserm U1259 MAVIVH & Université de Tours, France.

 

The severe form of Covid-19 is known to be associated with the excessive elevation of many cytokines, a condition termed “cytokine storm”. Therapy with biological agents intended to block these cytokines, for example anti-interleukin-6 or anti-interleukin-1 antibodies, was already tried, albeit with a limited success. However, a study recently published in the Journal of Allergy and Clinical Immunology  shows that there are at least two distinct types of cytokine storms induced by SARS-CoV-2 infection that are differentially associated with Covid-19 severity and mortality. As these distinct elevated cytokine profiles show up differently in different patients, this would imply the need for a personalized precision medicine approach to treat Covid-19. 

Apart from corticoid therapy, various treatments that were tested to reduce the COVID-19 associated cytokine storm seem to show disappointing results. The effectiveness of reducing mortality by blocking interleukins (for example, IL-6 and IL-1) has so far not been demonstrated. It has also been proposed that early-stage administration of type-I interferon therapy would slow SARS-CoV-2 replication, yet again with only limited reduction in mortality. It is possible that this apparent low effectiveness could be explained by the lack of stratification of patients to receive different treatments adapted to their individual cytokine profile.

Orages Cytokiniques

© Guy Gorochov

To answer this question, Prof. Guy Gorochov’s team (CIMI Research Center, Sorbonne University / INSERM, Paris, France), in collaboration with Prof. Avidan Neumann’s bioinformatics group (Department of Environmental Medicine, University of Augsburg, Germany), studied the levels of a large number of cytokines in the blood of 115 COVID-19 patients at the day of hospitalization during the first wave of the pandemic. The results of this study were then confirmed by a second validation cohort comprising of 86 patients from the second wave of the SARS-CoV-2 pandemic in Paris1.

Analysis of the results demonstrated that when looking at each cytokine separately, their blood levels showed great heterogeneity for each individual patient. “By looking at all cytokines together, using a non-supervised bioinformatics method called principle component analysis (PCA), we were able to reduce the large multi-dimensional variation into a two-dimensional perspective of cytokine combinations”, says Prof. Avidan Neumann. “Thus, we identified two distinct cytokine profiles that appear in different levels according to disease severity”.

Moderately severe patients, who initially do not have a severe respiratory illness, develop a response dominated by type-I interferons, in a context of high viral load, and relatively lower levels of pro-inflammatory cytokines. Conversely, patients with critical respiratory severity show elevated levels of pro-inflammatory cytokines (various levels of IL-6, IL-8, IL-10 and TNF-). Unexpectedly, SARS-CoV-2 antigen levels were lower in the critically severe patients, while the interferon anti-viral response is also less prominent in these patients. “These results go against the notion that high COVID-19 severity is always associated with excessive viral replication”, says Prof. Gorochov.

Nevertheless, having a strong type-I interferon response is not always good. An important observation was that the risk of death one month after hospital admission was related in each group to the intensity of the particular cytokine signature typical for that group. In particular, in the moderate severity group mortality was predicted by higher type-I interferon levels, while in the critical severity group mortality was associated with higher pro-inflammatory cytokine levels. Of note, mortality in the critical severity group was best predicted by higher levels of interlukin-10, rather than interlukin-6 or interlukin-1, thus possibly explaining the low effectiveness of therapy blocking the latter cytokines. Moreover, “our results suggest new therapeutic avenues”, says Prof. Gorochov, “as a higher risk of death in the most severe patients requiring ECMO is associated with lower levels of interleukin-17 and interleukin-18, cytokines that are associated with antibacterial response, treatment to increase their levels may improve patients’ survival”.

Overall these results suggest that COVID-19 severity and mortality are associated not with one cytokine storm, but rather with at least two distinct cytokine profiles.

Particularly not only an elevated pro-inflammatory response is dangerous but also, in some patients, an exacerbated anti-viral interferon response is associated with higher risk for mortality.

On the one hand, these results indicate that it would not be necessarily beneficial to administer type-I interferons in patients with already highly elevated levels of these cytokines2. On the other hand, therapy with biological agents should be targeted to block specific pro-inflammatory cytokines that are shown to be elevated in individual patients, rather than a one-for-all therapy. Thus, Prof. Claudia Traidl-Hoffmann, head of the Department of Environmental Medicine at the University of Augsburg, suggests that “this implies a paradigm change in COVID-19 therapy, personalized precision medicine, based on cytokine profiling, should be used to optimize COVID-19 treatment”.

Furthermore, Prof. Neumann adds “generalization of these results to earlier timepoints, currently tested in our on-going Early-Opt project at the Uniklinikum Augsburg, will allow optimization of both public-health and clinical management of COVID-19”.

SARS-CoV-2: infection induces antibodies capable of killing infected cells regardless of disease severity

Posted on by Graziella Cara

 

SARS-COV-2

©AdobeStock

 

Drawing on epidemiological field studies and the FrenchCOVID hospital cohort coordinated by Inserm, teams from the Institut Pasteur, the CNRS and the Vaccine Research Institute (VRI, Inserm/University Paris-Est Créteil) studied the antibodies induced in individuals with asymptomatic or symptomatic SARS-CoV-2 infection. The scientists demonstrated that infection induces polyfunctional antibodies. Beyond neutralization, these antibodies can activate NK (natural killer) cells or the complement system, leading to the destruction of infected cells. Antibody levels are slightly lower in asymptomatic as opposed to symptomatic individuals, but polyfunctional antibodies were found in all individuals. These findings show that infection induces antibodies capable of killing infected cells regardless of the severity of the disease. The research was published in the journal Cell Reports Medicine on April 21st, 2021.

Nearly half of those infected with SARS-CoV-2 do not develop symptoms. Yet, the immune response induced by asymptomatic forms of COVID-19 remains poorly characterized. The extent of the antiviral functions of SARS-CoV-2 antibodies is also poorly characterized. Antibodies are capable of both neutralizing the virus and activating “non-neutralizing” functions. The latter include antibody-dependent cellular cytotoxicity (ADCC) and complement activation, which are major components of the immune response and play a key role in the efficacy of some vaccines. ADCC is a two-stage process in which infected cells are first recognized by antibodies, then destroyed by NK cells. The complement system consists of a series of plasma proteins that also enable the elimination of cells targeted by antibodies. The ability of antibodies to activate these non-neutralizing functions has been little described for SARS-CoV-2 infection so far.

The teams from the Institut Pasteur, the CNRS and the VRI (Inserm/University Paris-Est Créteil) initially developed new assays to measure the various antibody functions. They produced assays to study cell death induced by NK cells or by complement in the presence of antibodies. By analyzing cultures in real time using video microscopy, the scientists showed that NK cells kill infected cells in the presence of antibodies, demonstrating new antiviral activity employed by SARS-CoV-2 antibodies.

The scientists then examined the serum of patients with symptomatic or asymptomatic forms of COVID-19 with their new assays. They also used methods previously developed at the Institut Pasteur, such as the S-Flow assay, to detect SARS-CoV-2 anti-spike antibodies, and the S-Fuse assay, to measure the neutralization capacity of these antibodies

“This study demonstrated that individuals infected with SARS-CoV-2 have antibodies that are capable of attacking the virus in different ways, by preventing it from entering cells (neutralization) or by activating NK cells to kill infected cells (via ADCC). We therefore use the term polyfunctional antibodies,” explains Timothée Bruel, co-last author of the study and a scientist in the Institut Pasteur’s Virus & Immunity Unit[1] and at the VRI.

By comparing different groups of patients, the scientists then showed that asymptomatic individuals also have polyfunctional antibodies and that their response is slightly weaker than those of patients with moderate forms of COVID-19.

“The study reveals new mechanisms of action of SARS-CoV-2 antibodies and suggests that the protection induced by an asymptomatic infection is very close to that observed after a symptomatic infection,” concludes Olivier Schwartz, co-last author of the study, head of the Virus & Immunity Unit and at the VRI.

 

[1] Department of Virology (CNRS/Institut Pasteur)

COVID-19: Timing Issues Prevent SARS-CoV-2 Host Cells From Stopping Replication

Posted on by Graziella Cara

Cellules infectées par le SARS-CoV-2

SARS-CoV-2 infected cells (in green). The size scale corresponds to 10 µm. © Joe McKellar

Although the SARS-CoV-2 target cells in the respiratory tract produce antiviral molecules following infection, it is too late to prevent the virus from replicating. This is the conclusion drawn by researchers from Inserm, CNRS and Université de Montpellier at the Infectious Disease Research Institute of Montpellier. Their findings have been published in the Journal of Virology

Inserm researcher Caroline Goujon and her team have spent a long time studying viruses at the Infectious Disease Research Institute of Montpellier (CNRS/Université de Montpellier). When the COVID-19 epidemic emerged, Goujon and her colleague Olivier Moncorgé decided to focus on the novel coronavirus, initiating several projects – one of which fundamental, in an aim to understand how the target cells respond when infection strikes.

At a time when the scientific community still had questions about SARS-CoV-2, building knowledge on the early stages of infection to understand how the virus enters the body and how it can be blocked was essential.

 

In search of interferons

In their recent study, the scientists describe this response by the target cells in the respiratory epithelium. They began by exposing respiratory epithelial cells to the virus, analyzing its multiplication in the hours that followed. In parallel, they looked for the presence of interferons, which are antiviral molecules naturally produced by the cells in the event of infection.

What they found was a rapid increase in viral load after 48 hours and the high production of two types of interferons (type I and type III) 48 to 72 hours after infection. The production of these molecules is generally triggered by certain host cell proteins – known as sentinel proteins because their task is to detect the presence of viruses.

The researchers then used the CRISPR-Cas9 technique to delete the genes coding for the main sentinel proteins and found that the absence of one of the genes, MDA- 5, prevented the production of the interferons. However, this phenomenon had no impact on the replication of the virus. “With or without the production of these interferons, which are supposed to counteract the virus, replication took place in the same way in our epithelial cell model,” clarifies Goujon.

However, research by the team and many other groups shows that placing the target cells in contact with these same interferons in the hours preceding infection considerably reduces the ability of the virus to replicate, dividing the replication rate by at least ten.

“Therefore the antiviral activity of interferons is not to be called into question when it comes to SARS-CoV-2. Their inefficacy in our model is due to a problem of timing. Their release occurs too late to block viral replication,” she explains. In order to have a protective role and avoid viral replication, it appears important for their production to take place earlier.

 

Open up avenues of therapeutic research

This research also opens up new prospects when it comes to the severe forms of COVID. “We know from previous studies that natural interferon levels are low in patients with severe forms of COVID-19 compared to those with less severe forms. Stimulating the body’s production of interferons early on by activating the MDA-5 pathway could limit the risk of developing severe forms in some patients,” she adds.

Some research teams have already begun to study the early administration of interferons in a number of clinical trials. As for Goujon and her colleagues, they have already made a start on the next phase of the project: identify the genes in the target cells whose expression is stimulated by infection and which help to slow viral replication – thereby possibly opening up new therapeutic avenues.

A Toxin Causing DNA Damage Found in Patients with Urinary Tract Infections

Posted on by Graziella Cara

Bactérie E Coli

During a urinary tract infection, uropathogenic Escherichia coli bacteria (in red, their DNA) form bacterial communities within superficial cells of the bladder (in blue, their nuclei; in green, their cellular sugar content), here 6 hours following an infection reproduced in mice. © Inserm/Motta, Jean-Paul/Chagneau, Camille

Urinary tract infections affect over 50% of women, in some cases recurrently. E. coli bacteria are very often implicated in their development. For the first time, researchers from Inserm, Toulouse University Hospital, INRAE, Université Toulouse III – Paul Sabatier and École nationale vétérinaire de Toulouse have identified the presence of a toxin produced by these bacteria in the urine of patients, which is thought to damage bladder cell DNA. These findings pave the way for new reflection on how to refine the treatment of patients prone to recurrent urinary tract infections. The study was published in Plos Pathogens on February 25, 2021.

Every year, 150 million people are affected by urinary tract infections. These are more common in women, with more than one in two experiencing them at some point in their lives. This represents a major public health problem, especially since the frequent need for antibiotic treatment is promoting the emergence of antibiotic resistance.

Urinary tract infections develop when the urogenital area is contaminated with bacteria from the gut microbiota. Escherichia coli (E. coli) bacteria are implicated in 80% of these infections[1] and have been the subject of several years of study by Eric Oswald and his team at the Digestive Health Research Institute (Inserm/INRAE/Université de Toulouse III Paul Sabatier/École nationale vétérinaire de Toulouse) in collaboration with various research teams in Toulouse.[2]

The scientists are particularly interested in the virulence factors of these bacteria, namely their ability to infect or damage the tissues of the host. They had already shown that under certain conditions E. coli in the intestinal tract can produce a toxin, colibactin, which is associated with an increased risk of colorectal cancer. In this new study, the team analyzed the urine samples of 223 adults with a urinary tract infection linked to the presence of E. coli and who were being treated in the emergency room of Toulouse University Hospital.

They identified a biomarker reflecting the presence of colibactin produced by the E. coli in at least 25% of the urine samples collected. This is the first time that this toxin has been identified in the context of a urinary tract infection and that researchers have provided direct evidence of its production during infection in humans.

DNA damage in mice 

In an attempt to better understand and characterize the effects of colibactin in the context of urinary tract infections, the researchers turned to animal models, showing in mice that the toxin is produced during urinary tract infection with E. coli and that it induces damage to the DNA in the bladder mucosa cells.

“These experiments allow us to step outside of a highly theoretical framework and show that, during a urinary tract infection, colibactin can have a genotoxic effect: the damage to the DNA does not completely repair itself and genetic mutations can occur. While we can only speculate on the impact of these mutations at this time, it is likely that they are linked to an increased risk of bladder cancer,” clarifies Oswald.

While these findings in animal models cannot in their current state be applied to humans, the researcher and his team believe that they could nevertheless lead to more extensive and targeted monitoring of people who are prone to recurrent urinary tract infections.

In addition, a better understanding of the links between gut microbiota and recurrent urinary tract infections is considered a priority. “We could consider implementing more specific management of patients suffering from regular urinary tract infections, with systematic screening for colibactin markers in their urine.And, more proactively, propose therapeutic approaches aimed at modulating the composition of their gut microbiota, which represents the main reservoir for the E. coli implicated in these infections,” emphasizes Oswald.

More particularly, the team is working on several research projects surrounding probiotics and the intestinal reservoir to limit harmful populations of E. coli in the microbiota and promote the emergence of “good bacteria”. A domain in which they have patented with Inserm-Transfert a non-pathogenic strain of E. coli that is capable of waging “biological warfare” on uropathogenic strains.

 

[1] This is referred to as uropathogenic Escherichia coli (UPEC).

[2] In particular, the coordination of a French National Research Agency (ANR) project in partnership with the company VibioSphen and an Inserm team working on iron metabolism.

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

Posted on by Graziella Cara

 

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

Focusing on Viral Load to Understand Progression to Severe COVID-19

Posted on by Graziella Cara

SARS-CoV-2 infected cell © Sébastien Eymieux and Philippe Roingeard, INSERM – Université de Tours

What are the factors predicting progression to severe forms of COVID-19? One year into the pandemic, this question remains a key research subject, and one that scientists from Inserm and Université de Paris decided to explore further by studying the link between viral kinetics and disease progression. This research is based on data from the Inserm-sponsored French COVID cohort, and has been published in PNAS.

While some patients infected with SARS-CoV-2 only have mild symptoms of COVID-19, a minority will go on to develop severe forms of the disease. A better understanding of the factors that determine this progression is essential if we are to improve their treatment and reduce mortality.

A team led by Inserm researcher Jérémie Guedj at the IAME laboratory (Inserm/Université de Paris) analyzed the biological data of 655 patients hospitalized for SARS-CoV-2 infection, and who were participants in the French COVID cohort.

The aim was to help elucidate the link between viral kinetics – the amount of virus present in the nasopharyngeal compartment over time – and the progression of the disease.

Their study has highlighted two essential points. The first is that the older the patient, the longer he or she takes to eliminate the viral load from the nasopharyngeal compartment. The second is that this viral dynamic is associated with mortality.

While viral load is certainly not the only factor in progression to severe disease and death, it does play an important role. Although COVID-19 is often described as an inflammatory disease, these virological aspects must also be taken into account in the treatment and support of hospitalized patients.

As a consequence, this research also highlights the need for continued research into the development of antiviral treatments.

In particular, the scientists used modeling to show that shortening the time to viral clearance by administering treatment upon hospitalization could significantly improve prognosis, especially in the most elderly.

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