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Category: Immunology, inflammation, infectiology and microbiology

Tuberculosis: children hospitalized with severe pneumonia in high-incidence countries should be screened for TB

Posted on by newround

© Copyright TB-Speed

Tuberculosis affects 1 million children each year; less than half of them are diagnosed and treated for the disease, which leads to more than 200,000 deaths. In a new study, researchers and clinicians from the TB-Speed consortium funded by global health agency Unitaid and led by the University of Bordeaux, in collaboration with the French Research Institute for Sustainable Development (IRD) and MU-JHU (a research collaboration between Makerere University and John Hopkins University in Uganda), showed that screening for tuberculosis at the time of hospital admission was feasible in children with severe pneumonia.

In addition, screening with a molecular test called Xpert Ultra improved the diagnosis of tuberculosis in children in countries with high incidence of the disease. The results of the study argue for a more systematic use of the Xpert Ultra in these children, especially in those suffering from severe acute malnutrition. They also confirm the importance of tuberculosis as a cause of severe pneumonia. These findings were published on November 15th, 2022 in The Lancet Infectious Diseases.

In countries with a high incidence of tuberculosis, the disease can be a cause of severe pneumonia and can contribute to mortality in young children. Usually the diagnosis of tuberculosis is considered only in children presenting with prolonged symptoms, those failing antibiotic courses prescribed for community-acquired pneumonia, or those with a history of contact with an adult with tuberculosis disease. Thus, many tuberculosis cases are missed or diagnosed with delays, which can result in poor outcomes and death.

However, young children presenting with tuberculosis-related severe pneumonia can have acute symptoms and would not be considered as presumptive tuberculosis cases. In this context, the TB-Speed consortium made the hypothesis that a tuberculosis screening in young children admitted with severe pneumonia with immediate treatment initiation for those who tested positive could reduce mortality of severe pneumonia related to tuberculosis.

TB-Speed Pneumonia is the first large-scale international cluster-randomized trial to assess the effect of doing systematic molecular tuberculosis detection in addition to the World Health Organization WHO standard of care in children admitted with severe pneumonia. The study, funded by Unitaid and the Initiative, and sponsored by INSERM, was conducted in 16 tertiary hospitals across six countries with high tuberculosis incidence (Cote d’Ivoire, Cameroon, Uganda, Mozambique, Zambia and Cambodia).

It aimed to assess the impact on mortality of adding systematic molecular tuberculosis detection using the Xpert MTB/RIF Ultra (Ultra) assay performed on one nasopharyngeal aspirate and one stool sample to the standard of care recommended by the World Health Organization for children with severe pneumonia (that includes antibiotics course, oxygen when indicated and treatment of HIV infection and severe malnutrition). Hospitals were randomly selected to start molecular testing and the flow was organized in order to reduce time to results to 3 hours. All children with Ultra positive results were immediately started on tuberculosis treatment. Children were followed for 12 weeks after enrolment.

2570 children were enrolled in the study (1401 in the control arm and 1169 in the intervention arm) between March 2019 and March 2021. 95% of children had nasopharyngeal aspirates and 80% had stools collected and tested with Ultra.

Although this tuberculosis screening intervention did not lead to a reduction in 12-week all-cause mortality as compared to the standard of care, it increased the rates of tuberculosis detection and microbiological confirmation and reduced the time to treatment initiation.

In addition, mortality and tuberculosis diagnosis rates were four to five times higher in children with severe acute malnutrition as compared to those without severe acute malnutrition. The study also showed that collecting and testing nasopharyngeal aspirates and stool samples with Xpert MTB/RIF Ultra in highly vulnerable children was highly feasible and well tolerated.

Efficacy of a Meningococcal B Vaccine and a Preventive Antibiotic in Reducing the Risk of Sexually Transmitted Infections

Posted on by newround

Vaccination © Adobe Stock

The ANRS DOXYVAC trial, conducted by a research team from the Paris public hospitals group (AP-HP), Université Paris Cité, Inserm and Sorbonne Université in collaboration with AIDES and Coalition PLUS, demonstrates the efficacy of both a meningococcal B vaccine in reducing the risk of gonorrhea infection and the use of doxycycline as preventive intervention for sexually transmitted infections when taken within 72h after sexual intercourse. In the wake of these results and taking into account the recommendations of the data and safety monitoring board, the scientific leaders and sponsor have decided to discontinue the trial and recommend the provision of both interventions to all its participants. This study is sponsored and funded by ANRS | Emerging Infectious Diseases in partnership with Roche[1].

According to World Health Organization (WHO) estimates, over 374 million people each year are diagnosed with a sexually transmitted infection (STI), which includes bacterial infections such as syphilis, chlamydia and gonorrhea. These bacterial infections particularly affect young people, men who have sex with men (MSM), and ethnic minorities. They are responsible for impaired quality of life and can cause serious side effects during pregnancy with congenital syphilis, risks of infertility in women and globally increase the risk of HIV infection.

In recent years, an increase in these STIs has been observed in France, particularly among MSM, making them a major public health problem for which new means of prevention must be developed.

Over the past few years, several research teams worldwide have been studying the efficacy of antibiotics used as prophylaxis in reducing the risk of STIs. This concept of post-exposure prophylaxis was first evaluated in the ANRS IPERGAY trial, which demonstrated that doxycycline, when used within 72h after sexual intercourse, led to an approximately 70% reduction in the risk of infection with chlamydia and syphilis.

In parallel, a certain number of epidemiological studies have reported in recent years that people receiving the Bexsero® meningococcal B[2] vaccine may have a reduced risk of gonorrhea infection by around 30%[3].

ANRS DOXYVAC differs from the other trials by the evaluation in a prospective, randomized trial of the combination of post-exposure prophylaxis with doxycycline and vaccination with Bexsero®. This study has been conducted since January 2021 in MSM, highly exposed to the risk of STIs and having presented at least one STI in the year prior to their participation in it. These men also participate in the ANRS PREVENIR cohort for the prevention of HIV infection whose results have recently been reported in The Lancet HIV and which showed that taking PrEP on demand was as effective and safe as its daily administration in preventing HIV infection.

ANRS DOXYVAC therefore forms part of a global, combined prevention framework in association with other risk reduction measures (repeated HIV and STI screening, hepatitis A and B vaccinations, distribution of condoms and gel) and with the possibility of community support or therapeutic education. Over 500 volunteers living in the Paris region[4] were randomly assigned to four groups: one receiving post-exposure prophylaxis with doxycycline, the other vaccination with Bexsero®, the third a combination of the two interventions, and the fourth neither of the two interventions.

Following the results of the US DOXYPEP study – presented at the International AIDS Conference in July 2022 in Montreal – and following an analysis of the data on the incidence of STIs among the ANRS DOXYVAC study participants, conducted at the request of the data and safety monitoring board, it was found that:

  • The doxycycline group presented a significant reduction in the risk of syphilis and chlamydia infections. The incidence of gonorrhea infections was also significantly reduced.
  • The meningococcal B vaccine group presented a significant reduction in the risk of gonorrhea infection.

According to the recommendations of the data and safety monitoring board, the scientific leaders and ANRS | Emerging Infectious Diseases, as sponsor, have therefore decided to stop the study in its current form in order to make doxycycline and the meningococcal B vaccine available to all ANRS DOXYVAC participants, following validation by the regulatory and ethical authorities. The follow-up of the participants will continue until the end of 2023 to ensure that these prevention strategies are effective in the medium term.

The results of the study have been submitted for presentation at an international congress in early 2023.

According to the study’s coordinating investigator, Prof. Jean-Michel Molina (Department of Infectious Diseases at Saint-Louis and Lariboisière Hospitals AP-HP, and Université Paris Cité) :

“the concept of biomedical prophylaxis at the time of exposure to the risk of sexually transmitted infections as part of an expanded prevention offering is therefore validated. We owe this to all the study volunteers without whom it would not have been possible to demonstrate this efficacy.” He adds: “however, the efficacy observed must not overshadow the fact that condoms remain the cornerstone of STI prevention in general. It is by adding together all the prevention tools that have proved themselves that we will be able to effectively control STIs and achieve the WHO and UNAIDS objective for 2030, which is to reduce their incidence by 90%.”

“It is a major step forward in the fight against STIs. The results of ANRS DOXYVAC should bring about changes to the national and international recommendations for the prevention of these diseases. This research project in its collaborative form with the associations AIDES and Coalition PLUS is showing particular promise when it comes to the future implementation of the recommendations.” affirms Prof. Yazdan Yazdanpanah, Director of ANRS | Emerging Infectious Diseases.

 

[1] Roche Molecular System and Roche Diagnostics France provided – free of charge – the kits, consumables and reagents needed to detect chlamydia, neisseria and mycoplasma.

[2] Meningococcus B (Neisseria meningitidis) is a bacterium that can cause meningitis. It is close to gonococcus (Neisseria gonorrhoeae).

[3] Observational studies conducted in New Zealand, USA, Australia and Canada.

[4] The participants were enrolled at the following hospitals of the Paris public hospitals group (AP-HP): Saint-Louis, Tenon, Pitié-Salpêtrière, Bichat Claude-Bernard, Saint-Antoine, Hôtel-Dieu, Necker, Garches, and Lariboisière.

Highly Effective Memory B Cells Localized in the Lungs

Posted on by Graziella Cara

Researchers showed that memory B cells can be localized in the lungs. © Adobe Stock

How can we increase the efficacy of vaccines used to protect against viral respiratory diseases such as influenza and COVID-19?  Scientists from Inserm, CNRS and Aix-Marseille Université at the Center of Immunology Marseille-Luminy are opening up new prospects in the field, with the triggering of memory B cells directly in the lungs looking to be a promising avenue. At present, the vaccines are administered intramuscularly and do not trigger the appearance of these cell populations. This research, which enhances fundamental knowledge in the field of immunology, has been published in the journal Immunity.

Memory B cells are immune cells produced primarily in the lymph nodes and spleen following infection. They persist for a long time in these regions and retain the memory of the infectious agent. If the body is confronted with the same agent in the future, these cells are immediately mobilized and rapidly reactivate the immune system for effective protection of the individual.

Following extensive research into these memory B cells, researchers discovered three years ago that they could also be localized in the lungs. The team led by Inserm researcher Mauro Gaya and his colleagues from the Center of Immunology Marseille-Luminy (AMU/CNRS/Inserm) and the Center for Immunophenomics (AMU/CNRS/Inserm) went further in order to describe the nature and functioning of this specific immune cell population.

The aim was to better understand these cells and their involvement in the long-term immune response against respiratory infections. For this, the scientists worked with two mouse models of infection: the influenza and Sars-CoV-2 viruses.

 

“Bona fide” and “bystanders”

They used fluorescent markers to track the appearance of memory B cells after infection, following which they performed a single-cell transcriptome analysis[1]. “These techniques enabled us to precisely localize these cells in the lungs of our animal models and describe their gene expression profile cell by cell to study their function,” explains Gaya.

Approximately ten weeks after inoculation of the virus and after its elimination from the body, the team observed the formation of groups of memory B cells in the bronchial respiratory mucosa, in a strategic position allowing them to be directly in contact with any new virus entering the lungs.

Furthermore, this research suggests that there are two subpopulations of memory B cells expressing different genes, known as “bona fide” and “bystanders”, with the “bona fide” cells having a particular affinity for the virus that triggered their appearance. In the event of new encounters with this pathogen, they immediately differentiate into plasma cells[2] and secrete highly specific antibodies against the virus.

Conversely, the “bystanders” do not directly recognize the virus but bind thanks to a specific receptor to the immune complexes formed by the antibodies that are produced by the “bona fides”.

The “bystanders” can therefore enable cross-reactions by increasing the response of different “bona fide” populations against several types of viruses. “What we have is a two-tier system that enables a synergistic effect and increases the efficacy of the anti-viral memory response in the lungs,” explains Gaya.

In addition to advancing fundamental knowledge in immunology, the research team sees in these findings a longer-term way of improving the efficacy of influenza or COVID-19 vaccines.

These findings could in fact form the basis for new research into the way vaccines are administered. “The hypothesis is that by intranasal vaccination, we could mimic the natural entry pathway of the virus, mobilize these lung memory B cells to block the virus as soon as it reaches the respiratory tract in the event of an infection. In this way, we could combat severe forms and also better protect against infection,” concludes Gaya.

 

[1] Single-cell transcriptome analysis: a technique used to study the genes expressed in each cell of a sample

 [2] Plasma cells:B cells that have reached a stage of terminal differentiation during which they produce antibodies

Phage Therapy: A Model to Predict Its Efficacy against Pathogenic Bacteria

Posted on by Graziella Cara

Photo (colorized) of scanning electron microscopy of a bacterium lyzed by the phages (© L. Debarbieux, Institut Pasteur; M. and C. Rohde, Helmholtz Centre for Infection Research).

Antibiotic resistance represents a major public health challenge, associated with a high mortality rate. While bacteriophages – viruses that kill bacteria – could be a solution for fighting antibiotic-resistant pathogens, various obstacles stand in the way of their clinical development. To overcome them, researchers from Inserm, Université Sorbonne Paris Nord and Université Paris-Cité at the IAME Laboratory, in close collaboration with their counterparts at Institut Pasteur and the Paris Public Hospitals Group (AP-HP), have developed a model to better predict the efficacy of phage therapy and possibly develop more robust clinical trials. Their findings have been published in Cell Reports.

The discovery of antibiotics had revolutionized the history of medicine in the 20th century, allowing us to effectively fight bacteria for the first time. However, antibiotic resistance – a phenomenon during which bacteria become resistant following mass, repeated use – has become a major public health issue in recent decades. Each year, these resistant bacteria are estimated to be responsible for 700,000 deaths worldwide. Yet the discovery of new antibacterial agents has been stagnating for several years.

In this context, phage therapy has recently generated renewed interest. This therapeutic approach involves the use of bacteriophages that target and destroy pathogenic bacteria whilst being unable to infect humans. While the concept has been in existence for a long time, its clinical development has been hampered by various limitations. Unlike “conventional” medicines, bacteriophages are complex biologics, whose action in the body, optimal dose, and most effective route of administration are difficult to study and anticipate.

In order to remove some of these obstacles, Jérémie Guedj’s research team at Inserm, in collaboration with Laurent Debarbieux’s team at Institut Pasteur, has developed a new mathematical model to better define the interactions between bacteriophages and pathogenic Escherichia coli bacteria in animals and to identify the key parameters that influence the efficacy of phage therapy.

Supporting clinical development

Various data from in vitro and in vivo experiments were used to construct this model. In particular, the researchers used the bacteriophages’ infection parameters determined in the laboratory (for example, the duration of the infectious cycle of the bacteria, the number of viruses released when a bacterium is destroyed…) and information collected during experiments using a mouse model of lung infection.

Some of the animals were infected with a bioluminescent strain of E. Coli (in order to best monitor it within the body). Among them, some were treated with bacteriophages at different doses and using different routes of administration. The quantities of bacteria and bacteriophages thus measured over time helped to feed the mathematical model and test which were the most important parameters for effective phage therapy. 

Using their model, the scientists show that the route of administration is an important parameter to consider when it comes to improving the animals’ survival: the more rapidly it brings the bacteriophages into contact with the bacteria, the more it is effective. In the animal model, the phage therapy administered intravenously was therefore less effective in comparison with the intratracheal route because fewer bacteriophages were reaching the lungs. On the other hand, when administered by intratracheal route, the model suggests that the dose of the medication given has little effect on the efficacy of the therapy.

Another important point is that this model incorporates data on the animals’ immune response in the context of phage therapy. The model confirms and extends the principle that bacteriophages act in synergy with the immune system of infected animals, enabling more effective elimination of pathogenic bacteria.

“In this study, we propose a new approach to streamline the clinical development of phage therapy, which otherwise continues to have its limitations. Our model could be reused to predict the efficacy of any bacteriophage against the bacteria it targets, once a limited number of in vitro and in vivo data are available on its action. Beyond phage therapy, the model could also be used to test anti-infective therapies based on the association between bacteriophages and antibiotics,” concludes Guedj.

Influenza: A New Avenue for Developing Innovative Treatments

Posted on by Graziella Cara

Cellules épithéliales respiratoires humaines

Human respiratory epithelial cells (in red) infected with an influenza virus (in green). © A. Cezard, D. Diakite, A. Guillon, M. Si-Tahar, PST ASB-Microscopy Department.

Seasonal influenza is a major public health issue because it continues to remain associated with considerable mortality, particularly among people who are elderly, immunocompromised, or both. It also has a significant socioeconomic cost. With vaccination and current treatments still being of limited efficacy, research teams are trying to develop new therapeutic approaches. At the Research Center for Respiratory Diseases in Tours, scientists from Inserm, Université de Tours and Tours Regional University Hospital have shown that in a context of influenza infection, a metabolite[1] called succinate, which is naturally present in the body, has an antiviral and anti-inflammatory action. These findings open up new therapeutic prospects based on the use of succinate derivatives. The study has been published in EMBO Journal.

Often considered a mild disease, influenza continues to cause the deaths of 10,000 to 15,000 people each year in France. The socioeconomic cost of the disease is also significant because it is associated with high levels of absenteeism and a major burden on hospitals.

Seasonal influenza vaccination is a central pillar of the preventive strategies deployed to reduce the number of cases and fight the disease. However, its efficacy can vary from year to year, depending on the influenza viruses in circulation and the suitability of the vaccine to them. Drugs that directly target the influenza virus are available for severe cases, but the window of time for effective action with these treatments is very short. What is more, influenza viruses have become resistant to their action.

In this context, the development of innovative therapies is a priority. While current treatments work by targeting certain components of the virus, Inserm Research Director Mustapha Si-Tahar and his colleagues at the Research Center for Respiratory Diseases are trying to better understand the host’s cellular and molecular responses to viral infection, with the long-term aim of developing novel therapeutic strategies aimed at strengthening these responses.

The role of metabolites in immune response

While metabolism1 has long been considered to be a purely energetic mechanism essential for cell function, recent research has shown that some metabolites can also regulate the immune response.

Based on these data, Si-Tahar’s team wondered whether an influenza infection could cause the reprogramming of the metabolism of the target cells of the virus and whether specific metabolites play an especially active role in the immune response.

In mice infected with influenza, the researchers observed that a metabolite called succinate accumulates in the lungs. A phenomenon which was then confirmed in humans by comparing respiratory fluids from intensive care patients with and without influenza pneumonia. The presence of succinate was found to be significantly higher in the influenza patients.

They then exposed cells from the pulmonary epithelium to succinate, thereby demonstrating that the molecule has antiviral activity by blocking multiplication of the virus. Succinate also helps to reduce the strong inflammatory response that is triggered in the lungs following infection with influenza.

The researchers also found that mice exposed to the virus receiving intranasal succinate are better protected against infection and have a higher survival rate than those that do not receive it.

In search of molecular mechanisms

In order to better understand these different phenomena, the scientists sought to decipher the molecular mechanisms behind the antiviral action of succinate.

This involved analyzing the impact of succinate on the various stages of the viral replication cycle and demonstrating that, while there is no influence on the early stages of the cycle (entry, transcription, and translation), there is an influence on a later stage. The findings show that this metabolite prevents a major structural protein of the virus, the “nucleoprotein”, from exiting the nucleus of infected cells, thereby preventing the assembly of the final viral particle and interrupting the multiplication cycle of the virus.

These data all point to the key role of succinate in controlling influenza infection, as well as its therapeutic value.

“Our research has an interesting outlook in that it potentially paves the way for the development of new antiviral treatments derived from succinate,” underlines Si Tahar[2].

Additional studies are needed in order to test the therapeutic potential of succinate and identify other metabolites of interest.

 

[1] Metabolism refers to all of the chemical reactions that take place inside the body’s cells. A metabolite is an organic substance derived from metabolism.

[2] In keeping with this research, Si-Tahar has since early 2021 coordinated a French National Research Agency (ANR) program entitled “Development of succinate-based formulations and analogues against SARS-CoV-2-induced respiratory infections and influenza viruses.” His team is also the beneficiary of an “ERS-RESPIRE4 Marie Skłodowska-Curie fellowship” to develop a project entitled “Succinate-Producing Probiotics as an Innovative Therapy for Viral Respiratory Infections: a proof-of-concept study”.

HIV: The Antibodies of “Post-treatment Controllers”

Posted on by Léa Surugue

VIH

© Adobe Stock

A very small percentage of people with HIV-1, known as “post-treatment controllers” (PTCs), are able to control their infection after interrupting all antiretroviral therapy. Understanding the fundamental mechanisms that govern their immune response is essential in order to develop HIV-1 vaccines, novel therapeutic strategies to achieve remission, or both. A recent study investigated the humoral immune response – also known as antibody-mediated immunity – in some PTCs in whom transient episodes of viral activity were observed. The researchers have shown their humoral immune response to be both effective and robust, which could help to control the infection in the absence of treatment. The findings of this study, carried out in collaboration with teams from Institut Pasteur, Inserm and Paris Public Hospitals Group (AP-HP) and supported by ANRS | Emerging Infectious Diseases and the National Institutes of Health (NIH), were published in Nature Communications on April 11, 2022.

A very small percentage of people with HIV-1 and who received early treatment maintained over several years have the capacity to control the virus over the long-term when their treatment is interrupted. However, the mechanisms of this control have not been fully elucidated.  

The team of researchers, led by Dr. Hugo Mouquet, director of the Laboratory of Humoral Immunology at Institut Pasteur (partner research organization of Université Paris Cité), conducted an exhaustive study in PTCs in order to characterize their humoral response (i.e. their production of B cells and specific antibodies), compared with non-controllers.

The scientists have shown that the humoral immune response profiles vary according to the activity of the virus observed in the subjects.

In PTCs who experience short episodes in which the virus resumes low-level activity after interruption of treatment, transient exposure to the viral antigens induces:

  • a strong anti-HIV-1 humoral response, involving more frequent intervention of HIV-1 envelope-specific memory B cells;
  • the production of antibodies with a cross-neutralizing action and which possess “effector” antiviral activities in which the innate immune cells recognize the infected cells bound to the antibodies, thereby inducing their elimination;
  • the increase in the blood of atypical memory B cells and subpopulations of activated helper T cells.

This specific, multifunctional, and robust humoral response could help to control their infection in the absence of treatment.

However, other PTCs in whom the virus continuously remains undetectable after treatment interruption do not develop a strong humoral response. The control mechanisms in these patients continue to be investigated in the VISCONTI study.

The discovery of these two types of humoral immune response, which depend on the profile of the PTCs, sheds new light on the phenomenon of HIV control. For Dr. Mouquet, researcher at Institut Pasteur and principal investigator of the study, “these findings show that early antiretroviral treatment can facilitate the optimal development of humoral immune responses, in some cases countering viral rebound after treatment interruption.” The example of the immune response of the PTCs having short episodes of “awakening” of the virus could even inspire novel therapeutic or vaccine strategies.

ANRS VISCONTI: to improve understanding of the HIV control mechanisms in “post-treatment controllers”

The “post-treatment controllers” whose samples were used for this research are part of the VISCONTI (Viro-Immunological Sustained COntrol after Treatment Interruption) study, coordinated by Dr. Asier Sáez-Cirión (Institut Pasteur) and Dr. Laurent Hocqueloux (Orleans Regional Hospital) and supported by ANRS for several years. This is the largest cohort of long-term “post-treatment controllers”.

It includes 30 patients who had received early treatment that was maintained for several years. Upon interruption of their antiretroviral therapy, they are able to control their viremia for a period exceeding 20 years in some cases. VISCONTI therefore provides the proof of concept of a possible and sustained state of remission for HIV-1-infected patients. It has paved the way for the development of novel therapies that target remission from the infection – if not its eradication. The objective is to enable people living with HIV-1 to stop their antiretroviral treatment on a lasting basis, while maintaining viremia at the lowest level and avoiding the risk of transmission of the virus.

Discovery of an immune escape mechanism promoting Listeria infection of the central nervous system

Posted on by Graziella Cara

vaisseau cérébral

Section of a cerebral vessel in an infected animal model containing infected monocytes adhering to endothelial cells. Listeria is marked in red, actin in white (including the actin tails propelling Listeria), nuclei in blue and macrophages in green. © Biology of Infection Unit – Institut Pasteur

Some “hypervirulent” strains of Listeria monocytogenes have a greater capacity to infect the central nervous system. Scientists from the Institut Pasteur, Université Paris Cité, Inserm and the Paris Public Hospital Network (AP-HP) have discovered a mechanism that enables cells infected with Listeria monocytogenes to escape immune responses. This mechanism provides infected cells circulating in the blood with a higher probability of adhering to and infecting cells of cerebral vessels, thereby enabling bacteria to cross the blood-brain barrier and infect the brain. The study will be published in Nature on March 16, 2022.

The central nervous system is separated from the bloodstream by a physiological barrier known as the blood-brain barrier, which is very tight. But some pathogens manage to cross it and are therefore able to infect the central nervous system, using mechanisms that are not yet well understood.

Listeria monocytogenes is the bacterium responsible for human listeriosis, a severe foodborne illness that can lead to a central nervous system infection known as neurolisteriosis. This central nervous system infection is particularly serious, proving fatal in 30% of cases.

Scientists from the Biology of Infection Unit at the Institut Pasteur (Université Paris Cité, Inserm) and the Listeria National Reference Center and WHO Collaborating Center led by Marc Lecuit (Université Paris Cité and Necker-Enfants Malades Hospital (AP-HP)) recently discovered the mechanism by which Listeria monocytogenes infects the central nervous system. They developed a clinically relevant experimental model that reproduces the different stages of human listeriosis, and involves virulent strains of Listeria[1] isolated from patients with neurolisteriosis.

The scientists first observed that inflammatory monocytes, a type of white blood cell, are infected by the bacteria. These infected monocytes circulate in the bloodstream and adhere to the cerebral vessels’ cells, allowing Listeria to infect the brain tissue.

The research team then demonstrated that InIB, a Listeria monocytogenes surface protein, enables the bacteria to evade the immune system and survive in the protective niche provided by the infected monocytes. The interaction between InlB and its cellular receptor c-Met blocks the cell death mediated by cytotoxic T lymphocytes, which specifically target Listeria-infected cells. InIB therefore enables infected cells to survive cytotoxic T lymphocytes.

This mechanism extends the life span of infected cells, raising the number of infected monocytes in the blood and facilitating bacterial spread to host tissues, including the brain. It also favors the persistence of Listeria in the gut tissue, its fecal excretion and transmission back to the environment.

“We discovered a specific, unexpected mechanism by which a pathogen increases the life span of the cells it infects by specifically blocking an immune system function that is crucial for controlling infection,” explains Marc Lecuit (Université Paris Cité and Necker-Enfants Malades Hospital (AP-HP)), head of the Biology of Infection Unit at the Institut Pasteur (Université Paris Cité, Inserm).

It is possible that other intracellular pathogens such as Toxoplasma gondii and Mycobacterium tuberculosis use similar mechanisms to infect the brain. Identifying and understanding the immune escape mechanisms of infected cells could give rise to new therapeutic strategies to prevent infection and also pave the way for new immunosuppressive approaches for organ transplantation.

This research was funded by the Institut Pasteur, Inserm and the European Research Council (ERC) and also received funding from the Le Roch-Les Mousquetaires Foundation.

[1] Uncovering Listeria monocytogenes hypervirulence by harnessing its biodiversity, Nature Genetics, February 1, 2016
Press release: https://www.pasteur.fr/en/listeria-hypervirulent-strains-cerebral-and-placental-tropism

MICA: A New Immune Response Gene That Predicts Kidney Transplant Failure

Posted on by Léa Surugue

Histological image of a kidney transplant rejection mediated by antibodies. Sophie Caillard/Jérome Olagne (Inserm U1109).

Although a kidney transplant is the only curative treatment for end-stage kidney disease, the risk of the patient’s body rejecting the graft means that success is not guaranteed. To reduce this risk, physicians are now able to look at a certain number of genetic and immunological parameters in order to evaluate the histocompatibility between donor and recipient – i.e. how compatible their organs and tissues are. Nevertheless, rejections continue to remain common, and many are unexplained. In a new study, researchers from Inserm, Université de Strasbourg and Strasbourg University Hospitals at Unit 1109 “Molecular Immunology and Rheumatology”, and their partners from the Laboratory of Excellence (LabEx) Transplantex, report that the MICA gene is a new histocompatibility gene, in that it helps to better explain and predict the success or failure of a kidney transplant. Their findings have been published in Nature Medicine.

Kidney transplant is currently the best way to treat patients with end-stage kidney disease. In France, an average of around 4,000 kidney transplants are performed each year (around 20,000 in the US). The kidneys mainly come from deceased donors, although the number of kidneys from living donors has been gradually increasing each year over the last two decades.

The possibility of rejection of the graft considered “foreign” by the recipient’s body is currently the main limitation of this procedure. While the use of immunosuppressant drugs[1] helps to reduce the risk, it does not eliminate it completely. “Chronic” rejection, which occurs over the years following the transplant, remains a major problem.

The discovery of the HLA system in the mid-20th century by French researcher Jean Dausset and his colleagues has enabled major advances. It is a set of proteins coded by the HLA genes – proteins which are present on the surface of our cells, particularly white blood cells.

Highly diverse and specific to each individual, this system makes it possible to assess the histocompatibility between donors and recipients – i.e. how compatible their organs and tissues are. The closer the HLA genes between donors and recipients, the lower the risk of rejection.

However, even when donor and recipient HLA genes are compatible, unexplained transplant rejections still occur. This phenomenon suggests that other as yet unidentified histocompatibility genes may play a role.

A role for the MICA gene

Researchers from Inserm, Université de Strasbourg and Strasbourg University Hospitals and their partners from LabEx Transplantex were therefore interested in a gene discovered almost thirty years ago by Seiamak Bahram[2] who coordinated this new research.

This gene, called MICA, codes for a protein expressed on several cell types. Previous studies had already suggested that this gene was important in predicting the outcome of a transplant, but the numbers of patients studied were insufficient (among other methodological limitations) in asserting that it was a histocompatibility gene. Furthermore, these studies did not focus on the entire MICA system, that is to say on both genetics (histocompatibility) and the serological aspects (presence of anti-MICA antibodies in the recipient’s blood).

In this latest study, the team studied MICA in over 1,500 kidney transplant recipients and their donors. Analyses of the MICA gene sequences show that when recipients and donors have a different version of the gene, the survival of the graft is reduced.

Furthermore, the researchers show that these MICA gene incompatibilities are responsible for the synthesis of antibodies directed against the donor’s MICA proteins, which are involved in transplant rejection. These antibodies are produced when the donor’s MICA proteins differ excessively from those of the recipient.

These findings suggest that MICA is a relevant histocompatibility gene to consider when envisaging a transplant, and that testing for anti-MICA antibodies may also be useful in predicting the success or failure of the graft. They must now be validated in large-scale prospective studies in which MICA will be considered in the same way as classic HLA genes.

“Following this research, we can now consider the inclusion in routine clinical practice of MICA gene sequencing and the identification of anti-MICA antibodies in patients prior to transplantation to assess histocompatibility with the donor and post-transplant to improve the prevention of rejection. Finally, we also envisage studying the role of MICA in the transplantation of other solid organs, such as the heart, lung and liver,” emphasizes Seiamak Bahram.

 

[1] Treatments that limit the action of the immune system used in autoimmune diseases and transplants.

[2] University Professor-Hospital Practitioner, Director of Inserm Unit 1109 and LabEx Transplantex, and Head of the Department of Clinical Immunology Laboratory at Strasbourg University Hospitals.

Discovery of an innate immunological memory in the intestine

Posted on by Graziella Cara

ILC3 intestinales

Intestinal ILC3s. Immunofluorescence staining of ILC3s (green) in the intestine (nuclei in blue and actin in red). © Nicolas Serafini – Institut Pasteur / Inserm

The innate immune system plays a crucial role in regulating host-microbe interactions, and especially in providing protection against pathogens that invade the mucosa. Using an intestinal infection model, scientists from the Institut Pasteur and Inserm discovered that innate effector cells – group 3 innate lymphoid cells – act not only during the early stages of infection but can also be trained to develop an innate form of immunological memory that can protect the host during reinfection. The study was published in the journal Science on February 25, 2022.

Combating Escherichia coli infections, which are responsible for intestinal diseases or gastrointestinal bleeding, is a major public health challenge. These bacteria, which are present in drinking water or food, can cause persistent diarrhea associated with acute intestinal inflammation. Consequently, enteropathogenic and enterohemorrhagic Escherichia coli are responsible for nearly 9% of child deaths worldwide.

The gut mucosa harbors a complex defense system that allows it to combat pathogen infection while maintaining tolerance to commensal microbiota, which are essential for the normal bodily function. This constant surveillance is performed by the innate immune system, which provides early defense in the initial hours after infection.

The adaptive immune system then develops a memory for the pathogens that it encounters by activating specific receptors expressed at the surface of B and T lymphocytes, thereby enabling the production of protective antibodies and inflammatory cytokines. Unlike the clearly established function of the adaptive system in long-term tolerance and protection, the role of the innate system in immune memory remains to be determined.

In 2008,[1] the team led by Inserm scientist James Di Santo (Innate Immunity Unit, Institut Pasteur/Inserm) described group 3 innate lymphoid cells (ILC3s) as a novel family of lymphocytes that were distinct from adaptive T and B lymphocytes. ILC3s play an essential role in the innate immune response, especially in the gut mucosa, by producing pro-inflammatory cytokines, such as interleukin (IL)-22.

The cytokine release activates the production of antimicrobial peptides by epithelial cells, thereby reducing the bacterial load in order to maintain the integrity of the intestinal barrier.

In this study, scientists from the Innate Immunity Unit (Institut Pasteur/Inserm) used an innovative protocol to expose the immune system to a time-restricted enterobacterial challenge based on Citrobacter rodentium (a mouse model of E. coli infection). They observed that ILC3s persist for several months in an activated state after exposure to C. rodentium.

During a second infection, the “trained” ILC3s have a superior capacity to control infection through an enhanced proliferation and massive production of IL-22.

“Our research demonstrates that intestinal ILC3s acquire a memory to strengthen gut mucosal defenses against repeated infections over time,” explains Nicolas Serafini, first author of the study and an Inserm scientist in the Innate Immunity Unit (Institut Pasteur/Inserm).

“The ability to “train” the innate immune system in the mucosa paves the way for improvements to the body’s defenses against a variety of pathogens that cause human diseases,” comments James Di Santo, last author of the study and Head of the Innate Immunity Unit (Institut Pasteur/Inserm).

This discovery demonstrates a new antibacterial immune defense mechanism and could lead, in the long term, to novel therapeutic approaches to treat intestinal diseases (IBD or cancer).

 

[1] Satoh-Takayama N. et al. Immunity 2008

A Novel Immunotherapy Approach Redirects Epstein-Barr Antibodies toward Disease-Causing Cells

Posted on by Léa Surugue

Microscopic visualization of a cancerous cell (nucleus in blue) treated with bi-modular fusion proteins (BMFPs) to which EBV antibodies (green) bind. © Jean-Philippe Semblat and Arnaud Chêne – JRU1134 (Inserm/Université de Paris)

 

Monoclonal antibody therapy can be very effective in treating numerous illnesses, such as cancers, chronic inflammatory conditions, and infectious diseases. However, it is costly and uses molecules that are complicated to produce. Therefore, it is essential to identify new therapeutic alternatives so that as many patients as possible get the treatments they need. That is why researchers from Inserm, Université de Paris, Sorbonne Université and CNRS1 have designed and tested a new immunotherapy approach that uses pre-existing antibodies directed against the Epstein-Barr virus – part of the herpes family of viruses and present in over 95% of the world’s population – in order to target and destroy pathogenic (disease-causing) cells. Their findings have recently been published in a study in Science Advances.

The principle is to redirect a pre-existing immune response against the Epstein-Barr virus (EBV) to target cells that we wish to destroy. The Epstein-Barr virus – which belongs to the family of herpes viruses – is transmitted predominantly through saliva, and over 95% of the world’s population is infected with it.

The vast majority of people have no symptoms, and the virus has the ability to persist chronically in infected individuals under the effective control of the immune system. As a result, EBV antibodies circulate in these people throughout their lives.

Developing a therapeutic tool based on the recruitment of these pre-existing EBV antibodies is of major interest in redirecting this immune response against target cells that are predefined according to the disease in question. This immunotherapy may be applicable in a very large number of patients due to the presence of EBV antibodies in almost everyone.

A promising new system

The researchers have developed specific proteins called bi-modular fusion proteins (BMFPs). These possess a domain that will bind specifically to an antigen expressed on the surface of the target cell to be destroyed. This domain is also fused to the Epstein-Barr virus EBV-P18 antigen against which IgG2 antibodies are already present in the patient. The recruitment of these antibodies on the surface of the target cells treated with BMFPs will then activate the body’s immune defenses, leading to the destruction of the target cells.

The researchers first tested this system in vitro using several target cells and showed that it effectively triggers different immune system mechanisms capable of eliminating target cells.

The BMFPs were then engineered to target an antigen expressed on the surface of tumor cells and were tested in an animal model of cancer. The results are promising because the treatment led to a significant increase in survival as well as the complete remission of cancer in some animals.

“These results position BMFPs as novel therapeutic molecules that may be useful in the treatment of multiple diseases. It is a highly versatile system, since it is easy to change the binding module and as such the antigen targeted in order to adapt the treatment to many diseases, in oncology, infectious diseases, and also autoimmune conditions,” explains Arnaud Chêne, Inserm Research Officer and last author of the study.

“BMFPs are much easier and faster to produce than whole monoclonal antibodies and do not require the use of sophisticated engineering to optimize their functions, thereby reducing costs and opening up access to a broader spectrum of patients,” adds Jean-Luc Teillaud, Emeritus Research Director at Inserm.

“Pending clinical trials in a variety of diseases ranging from cancer to malaria, the technology has already led to the filing of two patents.” explains Benoît Gamain, Research Director at CNRS.

 

1 Two laboratories took part in this research: Integrated Red Blood Cell Biology (U1134 Inserm/Université de Paris) and Center for Immunology and Microbial Infection (U1135 Inserm/Sorbonne Université/CNRS).

2 IgGs represent the main type of antibody found in the blood and are involved in the secondary immune response

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