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Toxoplasmosis: identification of a mechanism ensuring the immune surveillance of infection in the brain

Marquage de lymphocytes T cytotoxiques (CD8 en rouge et le marqueur de "résidence" CD103 en vert) logés dans le plexus choroïde d’un cerveau infectée par le parasite Toxoplasma gondii.Marking of cytotoxic T cells (CD8 in red and the ‘residence’ marker CD103 in green) lodged in the choroid plexus of a brain infected with the parasite Toxoplasma gondii. © Amel Aida

Toxoplasmosis is an infection caused by the parasite Toxoplasma gondii (T. gondii). In over one third of the human population, this parasite establishes a chronic infection of the brain which can have serious consequences in people with compromised immunity. Given the current lack of treatment to eliminate the persistent form of the parasite, a deeper insight into the immune mechanisms controlling this infection is essential if we are to hope to develop new therapeutic strategies. The study, conducted by Inserm researcher Nicolas Blanchard and his team at the Toulouse Institute for Infectious and Inflammatory Diseases (Infinity, Université Toulouse III Paul Sabatier, CNRS, Inserm), has shown that a category of immune cells known as resident CD8+ T cells plays a key role in detecting and neutralising the toxoplasmosis parasite in the brain. These findings, published in PNAS, make it possible to envisage new avenues for treatments to eliminate the persistent forms of toxoplasmosis.

Toxoplasmosis is a very common parasitic infection in humans. One in three people – or even one in two in some countries – has been exposed to this parasite in their lifetime. The parasite is transmitted by direct contact with the faeces of a feline carrier of T. gondii or by eating foods contaminated with it (poorly cooked meat, raw fruit and vegetables).

The consequences of this infection vary from one person to another. In healthy people, these are usually mild: while there may be fever and fatigue, the symptoms often go unnoticed. However, the parasite is not eliminated from the body. It can persist permanently in a so-called ‘latent’ form in the muscles, retina and brain. A growing body of data suggests that this chronic brain infection is associated with behavioural changes, or even an acceleration of neurodegenerative phenomena. What is more, in people with more fragile immunity, such as those with AIDS or using certain immunosuppressive treatments (e.g. in case of transplant), the consequences can be severe because the parasite can reactivate in the brain and cause potentially fatal inflammation (called brain toxoplasmosis or neurotoxoplasmosis).

At present, there is no treatment to eliminate the persistent form and permanently remove the parasite. A better understanding of the immune mechanisms that control the parasite, particularly in the brain, could suggest new therapeutic strategies aimed at stimulating natural immunity to the parasite in order to better contain or even eliminate it. 

The research team had previously shown that specific immune cells, called CD8+ T cells or ‘killer’ T cells, play a key role in controlling the parasite in the brain. However, we are dealing with a very diverse population of cells. For Inserm researcher Nicolas Blanchard and his team, it was crucial to identify which CD8+ T-cell subtype is involved, in order to elucidate the immune surveillance mechanisms of the parasite in the brain.

In 2009, a specific subtype of CD8+ T cells, referred to as ‘resident’ CD8+ T cells, was discovered.  These cells have the particularity of not patrolling the body but remaining stationary in the tissues, particularly the brain. The role of the brain-resident CD8+ T cell subpopulations in neutralising and eliminating the parasite had never previously been studied.

To study this role, the researchers used an animal model that mimics the latent T. gondii infection found in humans. Through selective elimination of the circulating or resident subpopulations, the team showed that the parasite is controlled in the brain by resident CD8+ T cells, as opposed to the other lymphocytes that patrol the lymphoid organs and tissues.

The researchers have also shown that the resident CD8+ T cells form thanks to signals issued by other immune cells, namely CD4+ T cells.

This is an interesting finding because it gives us a deeper insight into why people with HIV are potentially more vulnerable to brain toxoplasmosis. Indeed, HIV is known to reduce the number of CD4+ T cells, which could have a negative impact cascade on the formation of brain-resident CD8+ T cells, and therefore alter immunity to the toxoplasmosis parasite,’ explains Blanchard.

Based on these findings, the scientists will now be able to consider strategies in an attempt to improve the capacity of resident lymphocytes to fight brain infection.

‘Now that we have a better understanding of the mechanisms of surveillance of the toxoplasmosis parasite in the brain, we are conducting other research to understand the mechanisms deployed by the parasite to evade the control by CD8+ T cells and how we can try to neutralise these mechanisms,’ concludes Blanchard.

Respiratory allergies: newly discovered molecule plays a major role in triggering inflammation

AllergiesMicroscopic visualisation of immune cells (in green) activated by the alarmins TL1A and interleukin-33 during the onset of allergic inflammation in the lungs. ILC2s immune cells produce large quantities of interleukin-9, a key mediator of allergic inflammation. They are located near collagen fibres (blue) and blood vessels in the lung (red). © Jean-Philippe GIRARD – IPBS (CNRS/UT3 Paul Sabatier).

  • Inflammation plays a major role in allergic diseases, affecting at least 17 million people in France, including 4 million asthmatics.
  • One of the molecules that initiates this process in the respiratory tract has just been identified.
  • This molecule, a member of the alarmin family, is a major therapeutic target for the development of new treatments for respiratory allergies.

One of the molecules responsible for triggering the inflammation that causes allergic respiratory diseases, such as asthma and allergic rhinitis, has just been discovered by scientists from the CNRS, Inserm and the Université Toulouse III – Paul Sabatier. This molecule, from the alarmin family, represents a therapeutic target of major interest for the treatment of allergic diseases. The study, co-directed by Corinne Cayrol and Jean-Philippe Girard, is published in the Journal of Experimental Medicine on 10 April1.

The inflammation process plays a crucial role in allergic respiratory diseases, such as asthma and allergic rhinitis. Although the pulmonary epithelium, the carpet of cells that forms the inner surface of the lungs, is recognised as a major player in the respiratory inflammation that causes these diseases, the underlying mechanisms are still poorly understood.

A research team has identified one of the molecules responsible for triggering these allergic reactions, in a study co-led by two CNRS and Inserm scientists working at l’Institut de pharmacologie et de biologie structural (CNRS/Université Toulouse III – Paul Sabatier). This molecule from the alarmin family, named TL1A, is released by lung epithelium cells a few minutes after exposure to a mould-type allergen. It cooperates with another alarmin, interleukin-33, to alert the immune system. This double alarm signal stimulates the activity of immune cells, triggering a cascade of reactions responsible for allergic inflammation.

Alarmins, therefore, constitute major therapeutic targets for the treatment of respiratory allergic diseases. In a few years’ time, treatments based on antibodies blocking the TL1A alarmin could benefit patients suffering from severe asthma or other allergic diseases. In France, at least 17 million people are affected by allergic diseases2 with the most severe forms of asthma being responsible for several hundred deaths every year3.

 

  1. This study was supported by the ANR.
  2. According to the Ministère du travail, de la santé et des solidarités : https://sante.gouv.fr/sante-et-environnement/air-exterieur/pollens-et-allergies/article/effets-des-pollens-sur-la-sante; 13/04/2023
  3. According to Santé Publique France : https://www.santepubliquefrance.fr/maladies-et-traumatismes/maladies-liees-au-travail/asthme; 25/10/2023

HIV: early treatment, one key to remission

 HIV 3d illustration © Adobe Stock

People living with HIV need to take antiretroviral treatment for life to prevent the virus from multiplying in their body. But some people, known as “post-treatment controllers,” have been able to discontinue their treatment while maintaining an undetectable viral load for several years. Starting treatment early could promote long-term control of the virus if treatment is discontinued. Scientists from the Institut Pasteur, the CEA, Inserm, Université Paris Cité and Université Paris-Saclay, in collaboration with Institut Cochin[1] and with the support of MSD Avenir and ANRS Emerging Infectious Diseases, used an animal model to identify a window of opportunity for the introduction of treatment that promotes remission of HIV infection: it appears that starting treatment four weeks after infection promotes long-term control of the virus following the interruption of treatment after two years of antiretroviral therapy. These results highlight how important it is for people with HIV to be diagnosed and begin treatment as early as possible. The findings were published in the journal Nature Communications on January 11, 2024.

Research on the VISCONTI cohort, composed of 30 post-treatment controllers, has provided proof of concept of possible long-term remission for people living with HIV. These individuals received early treatment that was maintained for several years. When they subsequently interrupted their antiretroviral treatment, they were capable of controlling viremia for a period lasting more than 20 years in some cases. At the time (in 2013), the team leading the VISCONTI study suggested that starting treatment early could promote control of the virus, but this remained to be proven.

In this new study, the scientists used a primate model of SIV2 infection which allowed them to control all the parameters (sex, age, genetics, viral strain, etc.) that may have an impact on the development of immune responses and progression to disease. They compared groups that had received two years of treatment, starting either shortly after infection (in the acute phase) or several months after infection (in the chronic phase), or no treatment.

The reproducible results show that starting treatment within four weeks of infection (as was the case for most of the participants in the VISCONTI study) strongly promotes viral control after discontinuation of treatment. This protective effect is lost if treatment is started just five months later.

“We show the link between early treatment and control of infection after treatment interruption, and our study indicates that there is a window of opportunity to promote remission of HIV infection,” comments Asier Sáez-Cirión, Head of the Institut Pasteur’s Viral Reservoirs and Immune Control Unit and co-last author of the study.

The scientists also demonstrated that early treatment promotes the development of an effective immune response against the virus. Although the antiviral CD8+ T immune cells developed in the first weeks after infection have very limited antiviral potential, the early introduction of long-term treatment promotes the development of memory CD8+ T cells, which have a stronger antiviral potential and are therefore capable of effectively controlling the viral rebound that occurs after treatment interruption.

We observed that early treatment maintained for two years optimizes the development of immune cells. They acquire an effective memory against the virus and can eliminate it naturally when viral rebound occurs after discontinuation of treatment,” explains Asier Sáez-Cirión.

These results confirm how important it is for people with HIV to be diagnosed and begin treatment as early as possible.

Starting treatment six months after infection, a delay that our study shows results in a loss of effectiveness, is already considered as a very short time frame compared with current clinical practice, with many people with HIV starting treatment years after infection because they are diagnosed too late,” notes Roger Le Grand, Director of IDMIT (Infectious Disease Models for Innovative Therapies) and co-last author of the study.

“Early treatment has a twofold effect: individually, as early treatment prevents diversification of the virus in the body and preserves and optimizes immune responses against the virus; and collectively, as it prevents the possibility of the virus spreading to other people,” adds Asier Sáez-Cirión.

Finally, these results should guide the development of novel immunotherapies targeting the immune cells involved in the remission of HIV infection.

 

[1] Institut Cochin is a biomedical research center affiliated with Inserm, the CNRS and Université Paris Cité.

2 SIV: simian immunodeficiency virus only affects non-human primates. SIV infection of animals recapitulates the key features of human HIV infection.

These are the initial results of the p-VISCONTI study, which began in 2015 in collaboration with the institutions cited above and received funding from MSD Avenir and the support of ANRS Emerging Infectious Diseases as part of the RHIVIERA consortium.

First Digital Mapping of the Immune Cells Responsible for Allergies

mastocytesMarking of the different mast cell populations (in green and red), which are major players in allergic responses, on contact with neurons (white) in mouse skin. © Dr. Marie Tauber and Dr. Lilian Basso.

Allergic diseases affect up to one third of the world’s population, and their prevalence is on the increase. In order to develop more targeted and effective therapies, research is mobilizing to better understand the biological and cell mechanisms involved in the onset of allergies. Mast cells – a type of immune cell – is of particular interest to scientists and doctors, but there is little data about them at present. In a new study published in Journal of Experimental Medicine in July 2023, researchers from Inserm, CNRS and Université Toulouse III – Paul-Sabatier, at the Toulouse Institute for Infectious and Inflammatory Diseases (Infinity), broadened our understanding of these cells and created the first digital mapping of mast cells in humans. These findings open up avenues for the adaptation of therapeutic strategies.

Allergic diseases are a major public health problem, to the extent that the World Health Organization (WHO) has classified allergy as being the world’s fourth leading chronic disease. It is currently estimated that 25 to 30% of the population suffers from an allergy, be it food, skin or respiratory allergy, and this proportion could increase to 50% by 2050. A better understanding of the underlying biological mechanisms is a key step if we are to develop more targeted and effective therapies.

This is the goal of Inserm researcher Nicolas Gaudenzio and his team at the Toulouse Institute for Infectious and Inflammatory Diseases. In 2019, the scientists had published a first article in Nature Immunology, showing the crucial role played by immune cells known as “mast cells” in the initiation of eczema. This research has given rise to new therapies that are currently in development.

Mast cells remain poorly understood by scientists. We know that their functions go far beyond problems of allergies and that they can have roles that are either beneficial (such as in fighting bacteria) or not, depending on the pathology. Research has also led to their classification into two large families of mast cells: the CTMCs found mainly in the skin and the MMCs located mainly in the gut mucosa.

However, much remains to be learned about these cells that are complex to study, especially because it is difficult to extract them from tissue.

“If we are to understand how we can act on mast cells and block their harmful action in terms of allergic diseases, we need to improve our knowledge of these cells. This involves determining their location, if there are several types beyond the dichotomy which has traditionally been described, and whether their functions differ according to the tissues in which they are located,” points out Gaudenzio.

In this new study, the research team used more recent technologies to study mast cells more precisely in mice and humans. The scientists used the single-cell sequencing technique: they sequenced the RNA of individual cells from several organs in order to extract their individual “identity card”.

Analyzing human cells with this method reveals a much more complex image than has hitherto been described. Indeed, the cells of over thirty human organs were analyzed thanks to advanced techniques for exploring data banks and bioinformatics. The researchers thus identified not two but seven different subtypes of mast cells, with various characteristics and functions.

From this data, the team was able to create and enable open access to the first “digital mapping” of human mast cells, which allows any scientist to see at a glance which mast cell subtype is associated with which organ and learn more about its function.

 

mastocytes

This diagram shows, in a simplified way, the distribution of the different mast cell subtypes through different organs of the body.

This approach represents a major paradigm shift since the new mapping makes it possible, just by querying a database, to better understand the natural diversity of mast cells in allergic diseases, and thus open up a process of reflection on the need to adapt therapies to more precisely target the cell subtypes involved.

“This study is the first foundation stone of a vast building that is expected to transform the anti-allergy therapies and move towards a greater personalization of treatments, with more efficacy and fewer side effects. We will continue to supplement this mapping by studying mast cells in different disease settings, in treated and untreated patients alike, so that it is as precise as possible for the scientific and medical community that is working on allergies,” concludes Gaudenzio.  

Omicron BA.1 virus infection in vaccinated patients remodels immune memory

SARS-CoV-2

Cells infected with SARS-CoV-2 © Alberto Domingo Lopez-Munoz, Laboratory of Viral Diseases, NIAID/NIH

Teams from the internal medicine department of the Henri-Mondor AP-HP hospital, the Institut Necker – Enfants Malades, the Mondor Institute for Biomedical Research, the Institut Pasteur, Inserm, and the Paris-Est Créteil University studied immune memory after infection with the Omicron BA.1 variant in patients vaccinated with three doses of the messenger RNA COVID-19 vaccine. The results of this study ( MEMO-VOC) , coordinated by Dr Pascal Chappert and Pr Matthieu Mahévas, in collaboration with Dr Pierre Bruhns and Dr Félix Rey were published on August 4, 2023 in the Immunity review .

The Spike protein of SARS-CoV-2 1 Omicron BA.1 carries 32 mutations compared to the ancestral strain (Hu-1) originally identified. These mutations significantly alter neutralizing antibodies induced by natural SARS-CoV-2 infection and/or vaccination with an encoding mRNA vaccine.

Immune memory is a mechanism that protects individuals against reinfection. This defense strategy of the body, which is the basis of the success of vaccines, includes the production of protective antibodies in the blood (detected by serology) as well as the formation of memory cells (memory B lymphocytes 2 ), capable of quickly reactivate into antibody-producing cells upon re-infection.

The scientific literature has already shown 3,4 that the repertoire of memory B cells generated by two or three doses of mRNA vaccines contains neutralizing clones against all variants of SARS-CoV-2 up to Omicron BA.1.

The research team studied memory B cells after infection with SARS-CoV-2 Omicron BA.1 in 15 individuals previously vaccinated with three doses of the mRNA COVID-19 vaccine encoding the initial Spike protein of the virus. She followed them up to 6 months after infection with Omicron BA.1 to characterize the response of B lymphocytes, from the early immune reaction to the late onset of long-term memory.

This study reveals that infection with the Omicron BA.1 variant mainly mobilizes memory B cells recognizing common proteins between the initial Spike protein and Omicron BA.1 already present in the repertoire formed after vaccination, but few cells directed against specific BA.1 mutations.

Nevertheless, infection with Omicron BA.1 still induces a reorganization in the memory B cell repertoire without altering its diversity, and an improvement in the overall affinity of the memory B repertoire against the common structures of the Spike encoded in the original vaccine (Spike Hu-1) and that of the Omicron BA.1 variant. This reorganization of the memory repertoire is associated with a significant improvement in the ability to neutralize Omicron BA.1.

These results suggest that Omicron BA.1 virus infection in vaccinated patients remodels the memory B cell repertoire and enhances the ability of memory cells to recognize conserved SARS-CoV-2 epitopes and neutralize the virus.

Future vaccine strategies will nevertheless be needed to extend the immune response beyond conserved epitopes to deal with future antigenic variations of SARS-CoV-2.

This study has been labeled a National Research Priority by the ad-hoc national steering committee for therapeutic trials and other research on COVID-19 (CAPNET). The authors thank the ANRS | Emerging Infectious Diseases for its scientific support, the Ministry of Health and Prevention and the Ministry of Higher Education, Research and Innovation for their funding and support.

[1] SARS-CoV-2 protein that allows the coronavirus to enter human cells.
 
[2] Immune cells produced mainly in the lymph nodes and spleen following an infection. They persist for a long time in these regions and retain the memory of the infectious agent. If the body is confronted with them again, these cells are immediately mobilized and quickly reactivate the immune system for effective protection of the individual.
 
[3] Sokal, A., Broketa, M., Barba-Spaeth, G., Meola, A., Ferna´ ndez, I., Fourati, S., Azzaoui, I., de La Selle, A., Vandenberghe, A., Roeser, A., et al. (2022). Analysis of mRNA vaccination-elicited RBD-specific memory B cells re- veals strong but incomplete immune escape of the SARS-CoV-2 Omicron variant. Immunity 55, 1096–1104.e4. https://doi.org/10.1016/j. immuni.2022.04.002.
 
[4] Goel, R.R., Painter, M.M., Lundgreen, K.A., Apostolidis, S.A., Baxter, A.E., Giles, J.R., Mathew, D., Pattekar, A., Reynaldi, A., Khoury, D.S., et al. (2022). Efficient recall of Omicron-reactive B cell memory after a third dose of SARS-CoV-2 mRNA vaccine. Cell 185, 1875–1887.e8. https:// doi.org/10.1016/j.cell.2022.04.009.
 
[5] Part of a molecule capable of stimulating the production of an antibody.

Remission from HIV-1 infection: discovery of broadly neutralizing antibodies that contribute to virus control

Antibody fragments of EPCT112 bNAb (blue) discovered at the Institut Pasteur by Hugo Mouquet’s team, here forming a complex with the HIV-1 envelope protein (Env) (shown in yellow and orange

Some HIV-1 carriers who have received an early antiretroviral treatment during several years are able to control the virus for a long term after treatment interruption. However, the mechanisms enabling this post-treatment control have not been fully elucidated. For the first time, teams of scientists from the Institut Pasteur, Inserm and the Paris Public Hospital Network (AP-HP), supported by ANRS | Emerging Infectious Diseases, have investigated and revealed how neutralizing antibodies, including those described as broadly neutralizing, contribute to virus control. These key findings were published in the journal Cell Host & Microbe on July 10, 2023. A clinical trial involving the use of broadly neutralizing antibodies should begin in France before the end of 2023.

“Post-treatment controllers” is the term used to describe the rare HIV-1 carriers who, having initiated treatment early and maintained it for several years, are able to control the virus for years after that the treatment has been discontinued. These individuals were identified several years ago in part through the VISCONTI[1] study, which assembled the largest cohort of long-term post-treatment controllers in France. Although the mechanisms of viral control enabling the long-term remission from HIV-1 infection without antiretroviral therapy have not been fully elucidated, the identification of these cases provides a unique opportunity to refine our understanding of the factors associated to HIV-1 infection control.

A study conducted by the Institut Pasteur’s Humoral Immunology Unit led by Dr. Hugo Mouquet in collaboration with the team led by Dr. Asier Sáez-Cirión, Head of the Institut Pasteur’s Viral Reservoirs and Immune Control Unit, is now contributing to efforts to describe these mechanisms in more detail.

Asier Saéz-Cirión explains: “Our investigation published in 2020 on the immune response in post-treatment controllers marked a major first step in demonstrating an effective and robust antibody response to HIV-1 in some of these individuals, which may contribute to this control[2].This knowledge has now been further advanced by our new study. By investigating the role of antibodies in a specific “post-treatment controller” case with particularly high serum levels of broadly neutralizing antibodies, we discovered that remission was probably linked to the activity of this type of antibodies.

Hugo Mouquet describes the discovery: “Our study describes for the first time in a post-treatment controller a family of broadly neutralizing antibodies (bNAbs) targeting the HIV-1 envelope protein, of which the antibody EPTC112 is one of the most active member.

The antibody EPTC112 neutralizes about a third of the 200 viral variants of HIV-1[3] tested in vitro and is able to induce the elimination of infected cells in the presence of natural killer (NK) cells, the immune cells eliminating abnormal cells in the body.

This study therefore provides important insights on how neutralizing antibodies modify the course of HIV-1 infection in this individual from the VISCONTI cohort. Although the HIV-1 virus circulating in this subject was found to be resistant to EPTC112 neutralization due to mutations in the region targeted by this antibody, it was effectively neutralized by other antibody populations isolated from the blood of the individual. Hence, the study suggests that neutralizing antibodies from the EPTC112 family impose a selective pressure on the HIV-1 virus. Although the virus escaped the action of these bNAbs, it remained susceptible to the neutralization by other anti-HIV-1 antibodies produced in this individual. This observation suggests the existence of a cooperation between the various populations of neutralizing antibodies.

The fact that we discovered a potential link between the production of neutralizing antibodies, including bNAbs, and the HIV-1 control is exciting to better understand the underlying mechanisms of viral control, particularly by studying additional post-treatment controllers with similar profiles. Indeed, we wish to continue investigating on a short term whether the antibody responses in other ‘post-treatment’ controllers also contribute to long-term remission from the infection,” explains Hugo Mouquet.

This discovery paves the way for new avenues of HIV-1 therapy and fuels hopes of therapeutic approaches for increasing the chances of remission without antiretroviral treatment through the use of broadly neutralizing antibodies. To this end, a clinical trial involving the administration of broadly neutralizing antibodies[4] should begin in France before the end of 2023.

This Phase II trial conducted by the ANRS RHIVIERA consortium through a partnership between the Institut Pasteur, AP-HP, Inserm and the Rockefeller University in New York, will investigate the combination of an antiretroviral therapy in the primary infection phase with two long-acting HIV-1 bNAbs versus placebo to determine whether these antibodies contribute to establishing viral remission after antiretroviral treatment discontinuation. 69 patients in the primary HIV-1 infection[5] phase are planned to be enrolled. They will first receive a short-term antiretroviral treatment, followed by a therapy with the two bNAbs targeting two different regions of the virus envelope protein. It will be possible to stop therapy after a year of close monitoring based on a detailed set of criteria. This trial will enable us to determine whether this therapeutic strategy is able to induce a sufficient immune response to control the infection after the discontinuation of antiretroviral therapy,” concludes Hugo Mouquet.

VIH

Antibody fragments of EPCT112 bNAb (blue) discovered at the Institut Pasteur by Hugo Mouquet’s team, here forming a complex with the HIV-1 envelope protein (Env) (shown in yellow and orange) © Institut Pasteur

 

[1] HIV: The Antibodies of “Post-treatment Controllers”

[2] Transient viral exposure drives functionally coordinated humoral immune responses in HIV-1 post-treatment controllers study, Nature Communication, 11 avril 2022

[3] There are two types of HIV: HIV-1 and HIV-2 that differ from each other at molecular level. Variants occurring within these two types exhibit different levels of transmissibility, virulence and immunogenicity due to the various mutations associated with them.

[4] https://rhiviera.com/project/anrs-rhiviera-02/

[5] Primary infection: early phase of HIV-1 infection during which the viral load is high. The HIV virus invades the body, attacking the immune system and destroying its CD4 lymphocyte reservoirs.

A global overview of antibiotic resistance determinants

Proportion of third-generation cephalosporin resistance in Klebsiella pneumoniae, for blood infections, 2019 (data from ATLAS, Pfizer) © Institut Pasteur, Eve Rahbé

To understand the main determinants behind worldwide antibiotic resistance dynamics, scientists from the Institut Pasteur, Inserm, Université de Versailles Saint-Quentin-en-Yvelines and Université Paris-Saclay developed a statistical model based on a large-scale spatial-temporal analysis. Using the ATLAS antimicrobial resistance surveillance database, the model revealed significant differences in trends and associated factors depending on bacterial species and resistance to certain antibiotics. For example, countries with high quality health systems were associated with low levels of antibiotic resistance among all the gram-negative bacteria1 investigated, while high temperatures were associated with high levels of antibiotic resistance in Enterobacteriaceae. Surprisingly, national antibiotic consumption levels were not correlated with resistance for the majority of the bacteria tested. The results suggest that antibiotic resistance control measures need to be adapted to the local context and to targeted bacteria-antibiotic combinations. The results of the study were published in the journal The Lancet Planetary Health on July 10, 2023.

Antibiotic resistance (ABR) is currently one of the most urgent threats to global health. It is a natural phenomenon, but improper use of antibiotics is contributing to it by selecting resistance and complicating bacterial infection-control strategies.

Worldwide surveillance of antibiotic resistance, especially under the aegis of WHO has been set up, and several databases have been created to record ABR worldwide, with the long-term aim of improving understanding of the causes to help tackle the phenomenon.

Antibiotic resistance varies considerably depending on the bacterial species, but a recent study2 estimated that in 2019, 1.27 million deaths worldwide were attributable globally to ABR and ABR was associated with 4.95 million deaths.

To identify the main factors associated with worldwide antibiotic resistance dynamics, a multidisciplinary research team at the Institut Pasteur developed a statistical model and analyzed antibiotic resistance data from the ATLAS database, which contains data collected since 2004 in more than 60 countries on every continent. The scientists analyzed the data by testing a large number of determinants to reveal the main factors of antibiotic resistance and understand how they relate to the dynamics observed worldwide.

Research teams study how antibiotic resistance emerges in a bacterium in a Petri dish or in an individual, but we are currently lacking a population-level, global overview that can be used to investigate links between resistance and specific factors like national health system quality for different species of pathogenic bacteria. To understand the dynamics of antibiotic resistance, it needs to be studied at every level. That is what this study sets out to do,” explains Eve Rahbé, a PhD research student in the Institut Pasteur’s Epidemiology and Modeling of Bacterial Escape to Antimicrobials Unit and first author of the study.

The first stage of the study was to select relevant factors that could influence antibiotic resistance dynamics.

“Although some biological factors are known, it was also important for us to investigate hypotheses associated with socioeconomic and climate factors,” continues the scientist.

A total of eleven independent factors were selected, including health system quality (based on the GHS index3), antibiotic consumption and national wealth (GDP per capita), as well as data on travel and climate variables. Statistical models were then developed to study potential associations between the ATLAS data and the selected factors.

The analysis of global data for the period 2006-2019 initially revealed an increase in resistance to carbapenems for several species, although global trends were stable for other resistances. The study also demonstrated that the dynamics and factors associated with antibiotic resistance depend on bacteria-antibiotic combinations. Surprisingly, however, national antibiotic consumption was not significantly associated with resistance for the majority of bacteria tested (except for quinolone consumption for fluoroquinolone-resistant Escherichia coli and Pseudomonas aeruginosa and carbapenem consumption for carbapenem-resistant Acinetobacter baumannii).

Conversely, high health system quality was associated with low levels of antibiotic resistance in all the gram-negative bacteria1 tested. High temperatures were associated with high levels of antibiotic resistance, but only for Enterobacteriaceae (Escherichia coli and Klebsiella pneumoniae).

This study reveals the wide range of factors leading to antibiotic resistance among different pathogenic bacteria at global level, and the need to adapt resistance control approaches to the local context (country, transmission context) and the specific bacteria-antibiotic combination,” concludes Philippe Glaser, Head of the Institut Pasteur’s Ecology and Evolution of Antibiotic Resistance Unit and co-last author of the study.

“Our statistical model can be applied to other databases, such as the WHO database. Improving understanding of resistance determinants, which differ from one country to the next and probably even vary among regions in the same country, is crucial and will be useful in adapting public health measures,” concludes Lulla Opatowski, a Professor at Université de Versailles Saint-Quentin-en-Yvelines, scientist in the Epidemiology and Modeling of Bacterial Escape to Antimicrobials Unit and co-last author of the study.

This research was funded by the research organizations cited above, the LabEx IBEID and an independent research Pfizer Global Medical Grant. 

See the fact sheet about antibiotic resistance at pasteur.fr

1 Gram-negative bacteria are bacteria with two membranes that are more resistant to antibiotics because of the low permeability of their outer membrane.

2 Lancet, https ://doi.org/10.1016/S0140-6736(21)02724-0

3 GHS: Global Health Security Index

How Blood Stem Cells Detect Pathogens and Guide Immune Response

Cellule du système immunitaire infectée par BrucellaImmune system cell infected with Brucella (green); endocytosis compartment (blue). © CIML

Correct immune system function depends on the continuous supply of white blood cells derived from stem cells that reside in the bone marrow.  These are known as blood stem cells or hematopoietic stem cells. Researchers from Inserm, CNRS and Université d’Aix-Marseille at the Center of Immunology Marseille-Luminy have now discovered a new role played by these cells in immune response. In their article published in Journal of Experimental Medicine, they describe how they are able to recognize and directly interact with a bacterium called Brucella in the bone marrow, thanks to a receptor present on their surface. This is the first demonstration of the direct recognition of a living pathogen by the blood stem cells, which attests to their very early contribution to the immune response.

Blood stem cells, otherwise known as hematopoietic stem cells, are stem cells that reside in the bone marrow. They multiply and give rise to all blood cells, namely the red cells that transport oxygen and the white cells that participate in the immune response.

With regard to immune response, the blood stem cells had until now only been seen as the cells from which the white cells originate. However, a growing body of evidence suggests that they can also contribute directly and actively to the immune response. For example, recent data have shown that they can directly detect cytokines, which are proteins released during infection or inflammation.

In a new publication, a research team from Inserm, CNRS and Université d’Aix-Marseille led by Michael Sieweke and Jean-Pierre Gorvel[1] wanted to further the scientific knowledge in this area. The researchers succeeded in describing the mechanisms at work during the encounter between the blood stem cell and a specific pathogen: the Brucella bacterium, which is a mandatory reportable microorganism/toxin (MOT)[2].

Brucella causes an infectious disease called brucellosis (also known as Malta fever or Mediterranean fever), which is one of the most widespread zoonoses posing a significant threat to human health worldwide[3]. Brucella is an intriguing pathogen and very interesting for the scientists to study because of its ability to establish persistent and chronic infections and evade the immune response of its host[4].

The scientists found that the blood stem cells present in the bone marrow were able to detect Brucella. Their observations show that CD150, a specific receptor on the surface of the blood stem cells, interacts with Omp25, a protein present on the surface of Brucella.

bactérie BrucellaGraphic Summary of the Discovery. Thanks to the CD150 receptor on their surface, the blood stem cells in the bone marrow are able to detect Brucella. After recognizing it, they begin to produce more white blood cells. © CIML

 

“Our study reveals the mechanisms by which these blood cells are able to detect bacteria via a special receptor. We can consider this as a direct ‘handshake’ between the stem cell and the bacterium. Never had anyone imagined that the blood stem cell could recognize a living bacterium,” explains Sandrine Sarrazin, Inserm researcher and co-last author of the study.

The scientists then showed that this “handshake” leads to a rapid response by the stem cells, whereby they begin to produce more white blood cells. This is the first demonstration of the direct recognition of a living pathogen by blood stem cells and attests to a very early and unexpected contribution of these cells to the immune response.

 

How Brucella Uses Stem Cells to “Hack” the Immune System

The scientists then wondered whether this mechanism was more beneficial to the host or to the bacterium.

Thanks to meticulous observations, they found that Brucella directs the stem cells to produce the white blood cells it favors for infection. The bacterium is able to invade the white blood cells produced by the blood stem cells and use them to multiply and establish itself in the body. In this particular case, the stem cells therefore contribute to the spread of the bacterium.

“This research sheds new light on the sophisticated mechanisms that pathogens use to evade the immune system’s defenses. While the increased production of white blood cells would be beneficial if they could effectively fight infection, Brucella is able to exploit them in order to multiply,” explains Gorvel, one of the co-last authors of the study.

“This mechanism can be seen as an evasion strategy used by the bacterium to advance the infection,” summarizes Sieweke, another co-last author of the study.

The publication of this study marks an important step in understanding the complex dance between Brucella and the hematopoietic stem cells. It not only provides crucial information on the pathogenesis of brucellosis, but also opens up new avenues for the development of targeted therapeutic interventions.

“In addition to improving knowledge about how the immune response works, our study ultimately allows us to envisage the development of a targeted therapy capable of preventing the interactions between Brucella and the blood stem cell, preventing the spread of the bacteria in the body and helping patients with brucellosis,” concludes Gorvel.

 

[1] This research is the result of a collaboration between two research teams at the Center of Immunology Marseille-Luminy (CIML, CNRS/Inserm/Aix-Marseille Université): Michael Sieweke’s Stem cell and macrophage biology team and Jean-Pierre Gorvel’s Immunology and cell biology of pathogen/host cell interactions team.

[2] The Brucella experiment was therefore conducted at the Center for Immunophenomics (CIPHE) under biosafety level 3 conditions.

[3] The World Health Organization (WHO) has identified brucellosis as being one of the seven most neglected zoonoses, contributing to poverty, hindering development, and causing substantial economic losses in developing countries.

[4] Previous studies conducted at Gorvel’s laboratory had enabled crucial discoveries with the aim of elucidating the mechanisms underlying these phenomena.

Eating Broccoli to Limit Skin Allergies

brocoli

The scientists specifically focused on dietary compounds naturally present in cruciferous vegetables, such as broccoli. © Unsplash

The severity of skin allergies can vary depending on many environmental factors, including diet. However, the role of specific nutrients had not been well documented until now. In a new study, researchers from Inserm and Institut Curie at the Immunity and Cancer[1] unit have shown that the absence in the diet of compounds found in certain vegetables, particularly broccoli and cabbage, could worsen skin allergies in animal models. These findings, published in Elife, highlight the importance of a balanced diet alongside therapeutic interventions offered to patients.

Skin allergies are caused by an inappropriate immune response to compounds present in the environment, with the extent of their severity varying according to many factors, including diet. However, the impact of the different compounds present in food is still poorly understood, which complicates the use of nutrition-based strategies to alleviate patient symptoms.

In this research, the scientists focused on dietary compounds that act on a molecule present in the body called the aryl hydrocarbon receptor (AhR). Such nutrients are naturally present in cruciferous vegetables, such as broccoli.

While previous studies had already shown an association between these dietary compounds and the worsening of inflammatory bowel disease and neuroinflammation, their effect on allergic immune reactions had not been documented until now.

 

Worsening Allergies

The research team used a mouse model of skin allergy. Some of the animals were fed a diet containing no AhR-activating compounds in order to evaluate its potential impact on the severity of their allergy.

The researchers showed that the absence of these nutrients is associated with an increase in the skin’s inflammatory state and a worsening of the skin allergy, which did not occur in the mice whose diet contained those compounds.

The scientists wished to go further in order to understand the biological mechanisms of action of these nutrients. When the nutrients were absent, they observed the overproduction of a molecule called TGF-beta in the epidermis of the mice. This overproduction disrupts the normal functioning of a population of immune cells called “Langerhans cells”, which are exclusively present in the skin and act as a modulator of skin immune responses.

The scientists then validated these findings by showing that the AhR-activating compounds also control TGF-beta production in human skin cells.

“Our results suggest that an imbalanced diet could increase allergic skin reactions in humans through mechanisms that we have described precisely. In essence, we could say that our research helps to explain why eating vegetables such as broccoli and cabbage may limit the severity of skin allergies and why it is therefore important to include them in one’s diet,” emphasizes Inserm researcher Elodie Segura, who led this study at Institut Curie.

The findings of this study may also apply to other skin diseases in which inflammatory mechanisms are involved, such as psoriasis. Furthermore, they also open up interesting research avenues for improving the study of the gut-skin axis in the development of allergic diseases.

Based on these data, the research team now wishes to look at the role of AhR-activating dietary compounds in other inflammatory disease settings, such as tumors.

 

[1] Conducted at the Immunity and Cancer unit (Inserm, Institut Curie), this research was carried out with particular thanks to Institut Curie’s experimental pathology platform and new metabolomics and lipidomics platform.

Hypertension: A Mixture of Air Pollutants Could Cause Repeated High Blood Pressure Peaks

Pollution de l'airAir pollution is an acknowledged environmental factor in high blood pressure. © Adobe Stock

Air pollution is an acknowledged environmental factor in high blood pressure. It consists of a mixture of particles and gases whose combined effects on human health are not yet well known. A team from Inserm and Sorbonne Université, assisted by international collaborators, used continuous monitoring to study the daily life impact of a mixture of five air pollutants on the blood pressure of 221 MobiliSense[1] study participants in the Greater Paris area. With two models – one taking into account variations in ambient air pollutant levels, the other variations in the amounts inhaled – the researchers observed an association with acute repeated blood pressure increases. This study, published in Environmental Research, paves the way for a better understanding of the link between air pollution and hypertension.

Hypertension is a chronic disease that affects one in three adults. Linked to abnormally high pressure of the blood in the blood vessels, it can lead to cardiovascular, cerebrovascular, and even neurodegenerative complications.

Previous studies have shown that some air pollution molecules affect blood pressure and could therefore promote hypertension. However, in everyday life, the air pollution to which people are exposed generally consists of mixtures of air pollutants rather than a single component in isolation – mixtures that had been little researched until now.

An international team led by Basile Chaix, Inserm Research Director at the Pierre Louis Institute of Epidemiology and Public Health (Inserm/Sorbonne Université), wanted to characterize the effects on blood pressure of the daily-life exposure to a mixture of five air pollutants – black carbon, nitrogen dioxide (NO2), nitrogen oxide (NO), carbon monoxide (CO), and ozone (O3) – in 221 participants from the MobiliSense study.

In order to study the effects of this complex mixture, the research team developed new monitoring methods and used innovative measuring equipment. Each participant wore an ambulatory blood pressure measurement device[2], two portable sensors to continuously measure pollutants in the ambient air near the breathing zone, a GPS tracker to record mobility, and an accelerometer to measure physical activity and thus estimate the ventilation rate[3] (the volume of air inhaled or exhaled per unit of time). The measurements were taken over one day in the lives of the participants.

Their blood pressure was measured every 30 minutes in order to observe as closely as possible the time between variations in ambient air pollutant levels, the estimated amount of pollutants inhaled, and their potential impact on blood pressure.

Learn more about blood pressure and hypertension

Blood pressure results from the ejection of blood from the heart into the blood vessels and consists of the pressure it exerts on the vessel walls. It is characterized by two values:

  • the upper value or systole (systolic blood pressure), measured when the heart contracts. This pumps blood through the aorta to the peripheral arteries;
  • the lower value or diastole (diastolic blood pressure), measured when the heart relaxes. This enables the cardiac ventricles to receive the blood that enters the atria through the vena cava- and pulmonary veins.

Hypertension is when the resting systolic value is above 140 mmHg and/or the resting diastolic value is above 90 mmHg.

The researchers observed that when the levels of all the pollutants in the mixture increased within the 5 minutes prior to measuring blood pressure, there was an increase in systolic pressure (see box). A similar association was also found between an increase in the amount of pollutants inhaled within the 5 minutes prior to measuring blood pressure (related to an increase in the concentrations measured and/or physical activity and therefore in the ventilation rate) and an increase in systolic pressure.

“We chose to consider short windows of exposure (5 min, 15 min, 30 min, 1 hour) to study the time between exposure to pollution and blood pressure response, specifies Chaix. Here we see that the association is weaker when the exposure is observed over windows longer than 5 minutes, which indicates the immediacy of the blood pressure elevation in response to increased levels of air pollutants in the studied mixture,” adds the researcher. He continues: “These repeated increases in blood pressure linked to exposure to air pollutants in urban areas when out and about could contribute to a chronic rise in blood pressure, month after month, year after year. “

Another observation from these two models is that – when we consider the individual contribution of each pollutant to the effect of the mixture on blood pressure – ozone and black carbon present as being the greatest contributors to its increase.

With few existing studies having used these measurement and modeling methods to study mixtures rather than isolated pollutants, the research team clarifies that it does not currently have the possibility to compare its findings with other research, which means that they should be interpreted with caution.

However, should these findings be confirmed, it may be possible to extrapolate them to the populations of other major European cities whose pollution levels are similar to those of Greater Paris.

As for the implications of the study, Chaix concludes: “Our findings call for air pollution to be considered as a cause of hypertension and for the rollout of public policies aimed at reducing exposure to this pollution in everyday life – and particularly that of road traffic in the heart of our towns and cities. “

Next on the agenda is for the team to explore the physiological mechanisms and causes behind the associations observed in this study.

 

[1]The MobiliSense study is conducted on inhabitants of the Greater Paris area and aims to explore the effects of air and noise pollution exposure on cardiovascular and respiratory health.

[2]Unlike the blood pressure measurements taken when the individual is in a resting state, ambulatory blood pressure measurements are taken throughout the day and during the course of the individual’s activities using a wearable device.

[3]In previous studies, the team had shown that the amount of polluted air inhaled was not directly proportional to the levels of pollutants in the breathing zone but was also dependent on the ventilation rate, which varies with the intensity of physical activity. The ventilation rate was therefore estimated for each participant based on the accelerometer measurements.

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