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Month: February 2021

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

Improving immunotherapies for blood cancers: real-time exploration in the tumor

Posted on by Graziella Cara

Image taken in vivo following the injection of anti-CD20 antibodies, showing cancer cells (in magenta) and macrophages (in green) attacking tumor cells. © Institut Pasteur – Dynamics of Immune Responses Unit

Monoclonal antibodies are part of the therapeutic arsenal for eliminating cancer cells. Some make use of the immune system to act and belong to a class of treatment called “immunotherapies.” But how do these antibodies function within the tumor? And how can we hope to improve their efficacy? Using innovative in vivo imaging approaches, scientists from the Institut Pasteur and Inserm visualized in real time how anti-CD20 antibodies, used to treat B-cell lymphoma, guide the immune system to attack tumor cells. Their findings were published in the journal Science Advances on February 19, 2021.

Anti-CD20 antibodies are used in clinical practice to treat patients with B-cell lymphoma, a type of blood cancer. The treatment, often used in combination with chemotherapy, has been largely proven to improve the prognosis of patients but some respond less effectively than others. It is therefore critical to better understand how these therapies actually work to then be able to overcome their weaknesses.

Scientists from the Dynamics of Immune Responses Unit (Institut Pasteur/Inserm), led by Philippe Bousso, visualized the effect of the anti-CD20 antibody within the tumor seconds following injection and relied on tumor cells that change color as they die. Using this strategy, they demonstrate that macrophages play an essential role in the efficacy of the therapy, by ingesting tumor cells coated with antibodies.

“What surprised us was the observation that this elimination phase, which begins immediately after the injection of the antibody, became less effective after just a few hours,” explains Capucine Grandjean, lead author of the study. The scientists also showed that the quantity of macrophages in the tumor was very likely to be insufficient to destroy all cancer cells.

In revealing some of the weaknesses of these antibodies, the scientists have opened up new avenues for the development of next-generation therapies. In particular, increasing the presence and activity of macrophages in the tumor represents a promising strategy to boost the efficacy of these therapeutic antibodies.

This research was funded by the Institut Pasteur, Inserm and the ERC.

Communiquer pendant nos rêves, c’est possible !

Posted on by Graziella Cara

Was SARS-CoV-2 Already in France in November 2019?

Posted on by Graziella Cara

SARS-CoV-2 infected cells. © Sébastien Eymieux and Philippe Roingeard, Inserm – Université de Tours

Based on a retrospective analysis of serum samples from over 9,000 adults participating in the French cohort Constances[1], a study by Inserm researchers found that out of the 353 participants with positive SARS-CoV-2 antibody tests, 13 had had their samples taken between November 2019 and January 2020 – with confirmation by neutralizing antibodies testing. Investigations in 11 of these participants revealed the existence of symptoms possibly related to a SARS-CoV-2 infection or situations at risk of potential SARS-CoV-2 exposure. These findings published in European Journal of Epidemiology suggest the early circulation of the virus in Europe.

Right from the start of the pandemic, the entire research community has rallied to shed light on this novel virus. One of the tools at their disposal has been the possibility to use data from major health cohorts. It is thanks to the regular collection of samples from volunteers in the French general population-based cohort Constances since 2012 that the researchers were able to retrospectively study the serological status of SARS-CoV-2 antibodies in those participants.

This involved selecting all of the 9,144 serum samples collected between November 4, 2019 and March 16, 2020 from participants living in the 12 regions of metropolitan France. Serological analysis was performed using a commercial ELISA test to detect anti-SARS-CoV-2 (IgG) antibodies. These samples were then subjected to in-house micro-neutralization testing to detect neutralizing antibodies. Finally, those participants for whom both tests had been positive prior to February 1, 2020 were interviewed in order to identify potential exposure to SARS-CoV-2 infection. A trained investigator collected standardized information on clinical details (on the participant and his or her relatives), history of possible exposure (particularly history of travel in Asia), and any notable events occurring in close contacts (e.g. unexplained pneumonia).

Their findings: SARS-CoV-2 antibodies were detected in 353 participants (3.9%). The proportion of positive participants had increased from 1.9% in November and 1.3% in December to 5.0% in January, 5.2% in February, and 6.7% in the first half of March. Neutralizing antibodies were detected in 44 participants, 13 of whom had had their samples taken between November 5, 2019 and January 30, 2020. Eleven were the subject of further investigation, six of whom reported no symptoms in the weeks prior to having their sample taken. However, five participants had presented with signs of viral respiratory illnesses, and eight had had close contact with individuals who exhibited such signs or reported situations at risk of potential SARS-CoV-2 exposure.

This report suggests that SARS-CoV-2 virus circulation and infection could have occurred as early as November 2019 in France. It also confirms the value of monitoring large general-population cohorts in order to answer research questions, such as those arising during a health crisis of this magnitude.

 

[1] CONSTANCES is France’s largest general population-based cohort to date. It is comprised of a nationally representative sample of 215,000 adults aged 18 to 69 at the time of enrolment. Enrolment began in 2012 and serum samples are regularly collected during follow-up to be stored in a centralized biobank for future analysis.

The CONSTANCES cohort was funded under the “Investments in the Future” programs.

Maturation et persistance de la réponse lymphocytaire B mémoire anti-SARS-CoV-2

Posted on by Graziella Cara

 

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.

COVID-19 Vaccine Trials: Janssen’s Vaccine Candidate to be Tested by Covireivac

Posted on by Graziella Cara

Injecting a vaccine with a pre-filled syringe. © Inserm/Depardieu, Michel

The Phase 3 clinical trial of a COVID-19 vaccine is to be launched via Covireivac, a platform set up under the auspices of Inserm and the university hospitals to centralize COVID-19 vaccine trials in France. Janssen, the pharmaceutical division of the Johnson & Johnson group, has obtained the authorizations[1] needed for ENSEMBLE 2, a trial evaluating the efficacy and safety of vaccine candidate Ad26.COV2.S in the prevention of COVID-19 in adults. In France, 1175 volunteers out of those registered on Covireivac will enroll in this clinical trial that will be conducted in 30,000 people across the world.

To conduct the French component of the trial, eight centers[2] have been selected to enroll the 1175 volunteers, representing around 147 per center. The frequency of the disease will be compared between those having received the vaccine and those having received placebo. The aim is to determine whether the administration of two doses of the study vaccine is effective against COVID-19 and whether the vaccine protects against SARS-CoV-2 infection and disease.

The candidate developed by Janssen is based on an attenuated version of a virus that causes rhinopharyngitis in humans (adenovirus) in order to:

  • Produce just part of the COVID-19 virus, the spike “S” protein, which will be recognized by the immune system and induce an immune response
  • Block the multiplication of SARS-CoV-2 in the human body

This “non-replicating viral vector” vaccine is based on technology used in one of the Ebola vaccines, a product approved by the European Medicines Agency. It will be administered in the form of two intramuscular injections, with the second to be given 57 days (8 weeks) after the first. Details of the trial protocol are published on ClinicalTrials, a database of clinical studies conducted around the world.

The initial results available show that tolerability of the vaccine is good and that it induces the production of SARS-CoV-2 neutralizing antibodies in over 90% of the participants 29 days after vaccination and in almost 100% of them after 57 days.

Preliminary data show the vaccine to be 66% effective against COVID-19 and that the two-dose regimen (vs. the single-dose regimen) multiplied by 2 to 3 the quantity of antibodies produced against SARS-CoV-2.

The volunteers registered on Covireivac who have been selected to participate in this trial have already been contacted or will be shortly. To be eligible, the volunteers must, for example:

 

  • Be at least 18 years of age, healthy or with pre-existing medical conditions that are stable at the time of enrollment.
  • Be affiliated to a social security system.
  • Be capable of accepting and respecting the trial procedures and be capable of giving their free and informed consent.
  • For women of childbearing age, a negative pregnancy test is required before vaccine administration.

 

Ineligible for the trial are, for example, volunteers:

  • With unstable medical conditions.
  • Presenting with an acute illness or temperature ≥ 38°C within 24 hours before the first injection.
  • Having previously received a COVID-19 vaccine.
  • Having received a live attenuated vaccine within 28 days before the vaccination visit or another type of vaccine within 14 days before the vaccination visit.
  • Having received a clinical trial drug within 30 days to 6 months before enrollment, depending on its type.

 

“Once a vaccine becomes available in France, it is legitimate that volunteers ask themselves whether they wish to participate in a trial in which some of them will receive placebo. For obvious ethical reasons, for those who will soon be able to access the national vaccination campaign, the answer is that these eventualities will be taken into account in the upcoming protocol amendments and that the option will be there to get vaccinated as part of that campaign should they so wish, even if they have already been enrolled in the trial.” declares Odile Launay, Scientific Manager of Covireivac, whose coordination team is based at Hôtel-Dieu Hospital – AP-HP.

Even if vaccines are already approved in France, continuing the trials is essential if we are to further scientific knowledge, particularly regarding length of vaccine protection and quality of immune response.

Furthermore, in order to meet worldwide demand and the needs of the different populations, it is imperative to develop and have at our disposal several vaccines. Continued research also enables the development of products whose efficacies complement each other, are easier to administer, and possibly also cheaper to produce.

Covireivac

At the request of MSS and MESRI, Inserm has, in coordination with the hospitals and general practitioners, been tasked with setting up infrastructure to conduct clinical trials on COVID-19 vaccines in France. Driven by Inserm, this platform, named Covireivac, federates 24 clinical investigation centers (CICs) located in university hospitals across France, in close collaboration with the College of teachers in general practice. The clinical operational aspects of the various university hospitals are coordinated by the Paris hospital group AP-HP.

Covireivac is based on I-REIVAC, the existing national network for clinical investigation in vaccinology, which has been reinforced and extended for the occasion. This network has been labeled a network of excellence by F-Crin (France’s national clinical research infrastructure). The platform’s infrastructure is funded by MSS and MESRI.

 

[1] From France’s drugs regulator (ANSM) and the Île-de-France institutional review board (CPP)

[2] 2 centers in the Île-de-France region (Cochin Hospital AP-HP and Saint Antoine Hospital AP-HP); 3 in Occitanie, 1 in Nouvelle Aquitaine, 1 in Auvergne Rhône Alpes and 1 in Grand Est.

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