Image de microscopie à fluorescence de corps cellulaires des nocicepteurs innervant la peau. Les points verts représentent un ARN des nocicepteurs non-peptidergiques activés. © Lilian Basso/Inserm

Les troubles dermatologiques sont caractérisés par une inflammation et des démangeaisons sévères, et les traiter ainsi que les soulager représentent un véritable défi pour la recherche. Les mécanismes par lesquels certains neurones sensoriels, appelés nocicepteurs, intègrent les stimuli en périphérie du corps pour traiter simultanément l’inflammation et la démangeaison sont restés inexplorés pendant de nombreuses années. Dans une étude parue dans le journal Immunity, une équipe de l’Inserm, du CNRS et de l’Université de Toulouse, a montré que dans la dermatite de contact (une inflammation cutanée aiguë à l’origine de démangeaisons importantes), deux catégories de nocicepteurs avaient des fonctions biologiques distinctes. En effet, l’une permettrait de réguler les démangeaisons, tandis que l’autre semble agir directement sur l’inflammation provoquée par certains troubles dermatologiques. Ces résultats ouvrent la voie à de nouvelles stratégies thérapeutiques pour améliorer la vie des patients atteints de troubles dermatologiques.

La dermatite de contact (DC) est une maladie cutanée aiguë courante qui affecte environ 20 % de la population, et se caractérise par une hypersensibilité aux allergènes chimiques, une inflammation, et des démangeaisons sévères. Ces dernières résultent de l’activation dans la peau de terminaisons sensitives de plusieurs populations distinctes de neurones sensoriels regroupées sous le nom de nocicepteurs. Leur rôle est de transmettre la douleur et les démangeaisons au cerveau en passant par la moelle épinière, déclenchant des réponses comportementales comme les grattements.

Récemment, il a également été mis en évidence que les nocicepteurs sont capables de réguler la réponse de nombreux types de cellules immunitaires impliqués dans la dermatite de contact, notamment des neutrophiles (globules blancs qui détruisent les pathogènes). Cependant, le rôle individuel des différentes populations de nocicepteurs dans le développement de la DC restait jusqu’à maintenant inconnu.  

Dans une étude dirigée par Nicolas Gaudenzio et Lilian Basso, chercheurs Inserm à l’Institut Toulousain des Maladies Infectieuses et Inflammatoires (Inserm/CNRS/Université de Toulouse), les scientifiques ont pu identifier que différents circuits neuronaux contrôlent indépendamment la réponse inflammatoire et la démangeaison dans la DC.

L’équipe de recherche a combiné des approches génétiques et pharmacologiques dans un modèle de DC chez la souris. En isolant les neurones innervant spécifiquement la peau lors de l’inflammation cutanée, elle a comparé cellule par cellule leurs séquences d’ARN et a pu identifier deux populations de nocicepteurs activés de façon différentes : une population de nocicepteurs dits « non-peptidergiques », qui subissaient un changement au niveau de l’ensemble de leurs ARN, ainsi qu’une autre population de nocicepteurs dits « peptidergiques », qui ne subissait que quelques changements discrets.

Les chercheurs ont pu ensuite observer que la diminution des nocicepteurs peptidergiques au niveau d’une lésion cutanée était associée à une forte augmentation de l’inflammation avec une production locale accrue de neutrophiles, sans apaisement de la sensation de démangeaison. Au contraire, la diminution de la population de nocicepteurs non-peptidergiques était associée à une diminution drastique des démangeaisons sans aggravation de l’inflammation.

De façon surprenante, le rôle anti-inflammatoires des nocicepteurs peptidergiques semble en opposition avec leurs effets habituellement plutôt pro-inflammatoires dans d’autres contextes de pathologies cutanées, comme la dermatite atopique ou le psoriasis. « Les nocicepteurs peptidergiques semblent intervenir dans la régulation de la réponse immunitaire en limitant la production locale de neutrophiles, indique Lilian Basso. Cette capacité semble être fortement liée au contexte inflammatoire dans lequel ils sont activés, mais aussi au rôle des neutrophiles dans ce contexte : s’il est bénéfique, les nocicepteurs auront une action pro-inflammatoire, et s’il est néfaste, leur action sera plutôt anti-inflammatoire ».

L’équipe de recherche a aussi pu constater une fonction cicatrisante de la population de nocicepteurs non-peptidergiques dans les tissus cutanés lésés. « Il est connu que la cicatrisation des plaies, également présente dans les pathologies inflammatoires cutanées, s’accompagne de démangeaisons. Notre étude suggère que cette sensation de démangeaison pourrait être en fait le témoin de la contribution à la cicatrisation tissulaire des nocicepteurs non-peptidergiques » explique Tiphaine Voisin, chercheuse Inserm et première autrice de l’étude.

Ces résultats révèlent donc la présence de deux circuits neuronaux distincts et adaptatifs, qui réguleraient indépendamment l’inflammation via les nocicepteurs peptidergiques, et les démangeaisons de la peau via les nocicepteurs non-peptidergiques.

« Dans l’ensemble, nos résultats soulignent l’importance de considérer la plasticité des nocicepteurs lors de troubles dermatologiques afin de permettre une analyse plus précise des circuits neuronaux mis en jeu lors de la régulation de différentes manifestations de certaines pathologies. Cette nouvelle compréhension nuancée de la façon dont les nocicepteurs contribuent à l’inflammation et à la démangeaison pourrait ouvrir la voie à des stratégies thérapeutiques innovantes pour gérer simultanément l’inflammation et la démangeaison dans la DC et d’autres troubles cutanés », conclut Nicolas Gaudenzio.

Molecules passing through the colon epithelium via specialized pathways (goblet cells). In red: the molecules transported (antigens); in blue: the epithelium. © Institut Pasteur/Microbiome-Host Interactions/Clara Delaroque and Benoit Chassaing

A study conducted in mice by scientists from the Institut Pasteur and Inserm reveals that maternal consumption of dietary emulsifiers can have a negative impact on the gut microbiota of their offspring. These microbiota alterations are thought to significantly increase their risk of developing chronic inflammatory gut disorders and obesity in adulthood. The harmful transgenerational effects of maternal consumption of emulsifiers on the health of offspring highlight the need for additional research in humans on the impact of direct exposure to emulsifiers during early childhood. These findings were published in the journal Nature Communications.

Emulsifiers are food additives commonly used to improve the texture and shelf life of processed foods, such as dairy products, baked goods, ice creams, and also some powdered baby formulas. But little is known about their impact on human health, especially the intestinal microbiota.

In a study led by Benoit Chassaing, Inserm Research Director and Head of the Microbiome-Host Interactions laboratory (an Inserm unit at the Institut Pasteur), the scientists exposed female mice to commonly used emulsifiers (carboxymethyl cellulose (E466) and polysorbate 80 (E433)) for ten weeks before gestation, then throughout pregnancy and lactation. They then analyzed the impact on the intestinal microbiota of their direct offspring, who themselves had never consumed these emulsifiers. Results show that the offspring of mothers exposed to emulsifiers had significant alterations to their gut microbiota from the first weeks of life, the period during which the mother transmits part of her microbiota through close contact.

These alterations included an increase in flagellated bacteria, known to activate the immune system and trigger an inflammatory response, as well as a higher level of bacteria coming into closer contact with the gut mucosa. The scientists observed that this bacterial “encroachment” results in the premature closure of certain passages in the gut which normally allow bacterial fragments to cross the mucosa so that they can be recognized by the immune system and build the body’s tolerance towards its gut microbiota. In the offspring of mothers exposed to emulsifying agents, these passages close earlier than in the offspring of non-exposed mothers, disrupting communication between the microbiota and the immune system. In adulthood, such disruption leads to an exacerbated immune response and chronic inflammation, significantly increasing susceptibility to inflammatory gut disorders and obesity. The study therefore establishes a link in mice between early alterations to their microbiota – even in the absence of direct consumption of emulsifiers – and increased susceptibility to chronic conditions such as obesity and inflammatory gut disorders over the long term.

“It is crucial for us to develop a better understanding of how what we eat can influence future generations’ health. These findings highlight how important it is to regulate the use of food additives, especially in powdered baby formulas, which often contain such additives and are consumed at a critical moment for microbiota establishment. We want to continue this research with clinical trials to study mother-to-infant microbiota transmission, both in cases of maternal nutrition with or without food additives and in cases of infants directly exposed to these substances in baby formula,” comments Benoit Chassaing, last author of the study.

This research was supported by a Starting Grant and a Consolidator Grant from the European Research Council (ERC).

Phylogenetic tree constructed from bacterial (blue) and eukaryotic (green) SIR2 domain proteins. The proteins are divided into two subfamilies, one of which, the sirims, contains the immune SIR2 proteins, including SIRal.

What if the study of bacteria could illuminate our understanding of human immunity? In recent years, scientists have been exploring unexpected links between human proteins involved in the body’s defense mechanisms and certain bacterial immune proteins. Focusing on conserved immune domains originating from bacteria, termed “ancestral immune”, a team of researchers from Institut Curie, Institut Pasteur, and Inserm identified a novel human immune protein, SIRal. Published in Science on July 24, 2025, the study highlights the benefits of unraveling immune evolution, from bacteria to humans, to open promising avenues of research in immunotherapy.

It is widely assumed that scientists thoroughly mapped out the pathways of human innate immunity— the body’s first line of defense, which detects pathogens and triggers a rapid, protective response. However, the emerging field of ancestral immunity is challenging this long-held assumption. By exploring evolutionary links between bacterial and human proteins, researchers are finding that a significant number of proteins involved in human innate immunity are evolutionarily derived from bacterial immune defences. These proteins are not only structurally conserved: their immune functions have also been preserved—sometimes across billions of years of evolution.

SIRal, a prototypical ancestral immune module

In bacteria, the SIR2 (silent information regulator 2) protein domain plays a key role in defense against phages—viruses that specifically infect bacteria. When a phage invades a bacterium, SIR2 degrades a molecule essential for cell metabolism, leading to the death of the infected cell and the protection the rest of the bacterial population.

By reconstructing the evolutionary history of genes through phylogenetic analysis[1], a team led by Dr. Enzo Poirier, Inserm researcher and team leader at Institut Curie’s Immunity and Cancer Unit (Institut Curie, Inserm), and Dr. Aude Bernheim, head of the Molecular Diversity of Microbes Unit at Institut Pasteur, identified a human homologue of the SIR2 domain—SIRal. Results indicate that SIRal is a pivotal actor of innate immunity, through its ability to degrade NAD⁺, an essential metabolite involved in energy production.

Far from being a particularism of humans, SIRal proteins represent an ancient, well-shared family detectable in 19% of the eukaryotic genomes analyzed, spanning five major lineages. These findings confirm that bacterial-derived immune mechanisms are widely conserved across the tree of life, with potential implications for all eukaryotes.

In addition to the phylogenetic approach, Dr. Delphine Bonhomme (Poirier team), Hugo Vaysset (Bernheim team) and their colleagues demonstrated that SIRal acts as a central regulator of the TLR (Toll-like receptor) pathway —a family of receptors that detect pathogen-associated signals. This TLR pathway, regulated by SIRal, triggers the innate immune response, embodied by the expression of pro-inflammatory genes. The team showed that, without SIRal, the inflammatory response is severely impaired upon bacterial and viral infections.

“With SIRal, we show that protein modules inherited from bacterial immunity can play a central role in eukaryotic immune mechanisms, including in humans. The exloration of ancestral immunity thus gives us access to a previously unsuspected reservoir of immune mechanisms,” explains Enzo Poirier, Inserm researcher and team leader at Institut Curie.

“This discovery illustrates how evolution reuses ancient building blocks to create new functions: mechanisms that originated in bacteria billions of years ago still shape our immunity today,” adds Aude Bernheim, head of the Molecular Diversity of Microbes unit at Institut Pasteur.

A promising therapeutic target

Beyond its evolutionary implications, the discovery of SIRal could have clinical applications. Several autoimmune diseases are partly driven by the activation of TLR receptors. SIRal thus represents a novel therapeutic target, and its study could pave the way to innovative immunotherapies.

[1] Phylogeny is the study of evolutionary relationships between species, aiming to reconstruct their kinship from a common ancestor.

Mouse macrophages visualized using confocal microscopy, showing the nuclei (blue) and the actin network (orange). © Mónica Fernández Monreal, Bordeaux Imaging Center

Macrophages, key cells of the immune system, play a central role in cleaning the body by ingesting and destroying pathogens (bacteria, viruses, etc.) and damaged cells. Scientists from Inserm, CNRS and the University of Bordeaux, in collaboration with international teams, reveal that this well-known role is accompanied by another surprising ability: in order to support their activity and metabolism, macrophages are capable of sourcing nutrients directly via the breakdown of the ingested bacteria. This research, to be published in Nature, also shows that macrophages extract nutrients more effectively from dead bacteria than from living bacteria. These findings shed new light on the fate of the pathogens ingested by macrophages and open up new avenues for the development of innovative vaccines and antibiotics.

Nutrients are essential molecules for the body to produce energy, maintain its metabolism, and ensure its growth and development. They participate in the activation, functioning and differentiation of immune cells. Among the latter, macrophages are innate immune cells that contribute to the maintenance and correct functioning of the body’s tissues. To do this, these immune players are able to ingest various large particles, debris and pathogens, ranging from damaged or aged cells to bacteria and viruses, and break them down by digesting them; a phenomenon called “phagocytosis”.

While most mammalian cells consume nutrients from food, some have additional abilities that enable them to seek nutrients through alternative processes. For example, previous studies have shown that certain phagocytes[1] are able to extract nutrients from the dead cells they digested. However, until now, scientists did not know whether this particularity applied only to the phagocytosis of the body’s own cells, or whether it could also work to extract nutrients from phagocytosed pathogenic organisms (bacteria, viruses, etc.).

An international research group co-led by Johan Garaude, Inserm researcher in the Conceptual, Experimental and Translational Immunology – ImmunoConcEpT unit (Inserm/CNRS/University of Bordeaux), has studied the phagocytosis of bacteria by macrophages and its potential role in macrophage metabolism.

With this in mind, the scientists compared macrophage metabolism in different environments: in the presence of living bacteria, dead bacteria, and in the presence of a component of the membrane of these bacteria that is well-known for activating macrophages.

Their findings show that those macrophages having phagocytosed whole bacteria, whether living or dead, presented a very different metabolic activity linked to the use of nutrients than those activated only by the component of the bacterial membrane.

“This suggests that the role of the macrophages could go far beyond the detection and simple destruction of bacteria, analyzes Garaude: they appear capable of exploiting them as a source of nutrients to support their own metabolism and thereby fulfil the specificity of their role as immune system alarm.”

The research team has also shown that the effectiveness of this metabolic recycling depends on the viability of the bacteria. Dead bacteria prove to be more efficient resources than living bacteria: the macrophages having internalized dead bacteria presented better transport and use of the nutrients derived from their breakdown. Thus, those having phagocytosed dead bacteria had much better chances of surviving in nutrient-depleted environments, unlike those having phagocytosed living bacteria.

“This difference could constitute an advantage for the survival of macrophages in infected tissues, when nutrients are scarce because they are already consumed by rapidly reproducing bacteria,” explains Garaude.

The study shows that this differentiated mobilization of nutrients is orchestrated by a mechanism internal to macrophages[2]. A mechanism that is thought to have the role of restricting the removal of nutrients by the macrophage during the phagocytosis of a living bacterium. It could also limit the excessive accumulation of nutrients within the macrophage, when it is having to simultaneously digest a large number of bacteria.

“This could be a protective mechanism to prevent macrophages from using potentially dangerous molecules, derived from infectious agents, or to regulate the intensity of the inflammatory response to infection by limiting access to nutrients that could ‘boost’ it,” adds Juliette Lesbats, doctoral student from the University of Bordeaux and first author of this research.

“Our findings highlight the capacity of phagocytes to adjust their cell metabolism to the ‘nutrient potential’ represented by phagocytosed bacteria, explains Lesbats. They show how, when combined with the capacity to detect microbial viability, this ability makes it possible to regulate the metabolic adaptation of immune cells.” Although the importance of this mechanism in bacterial infections has yet to be explored, this study opens up promising new avenues for fighting antibiotic resistance or devising new vaccine approaches.

[1] Cells capable of phagocytosis.

[2] This concerns the mTORC1 intracellular signaling pathway.

Section of intestinal tissue with staining of immune cells. © Héloïse Rytter

Widely used by the food industry, emulsifiers – a type of food additive – are found in many daily foods (sliced bread, ice creams, crème fraîche, plant milks, etc.). Given their omnipresence in our diet, the health effects of their consumption have become a real public health issue. Benoit Chassaing, Inserm Research Director and leader of the Microbiome-Host Interactions team at Institut Pasteur (Inserm/Université Paris Cité/CNRS), has previously reported that by acting directly on our gut microbiota, these additives could promote the development of chronic inflammatory diseases and metabolic deregulations. In a new study published in Gut, he and his team developed a human microbiota modelling system capable of predicting each person’s sensitivity to an emulsifier, using a simple stool sample. This discovery paves the way for a personalised nutrition approach based on the gut microbiota in order to maintain good gut and metabolic health.

The food industry is making increasing use of many additives to improve the texture and extend the shelf life of its products. Several studies have reported their harmful effects on gut and metabolic health, linked to their interactions with our microbiota. In 2015, Inserm Research Director Benoit Chassaing looked at the effects on the microbiota and gut health of consuming an emulsifier, carboxymethylcellulose (CMC), commonly found in industrial brioches [sweet buns], sliced bread and ice creams[1]. The results of his research suggested that consuming this additive over the long term could have a negative impact on the microbiota and, as a consequence, promote chronic inflammatory diseases and metabolic deregulations.

Then, during a clinical trial on healthy volunteers, Chassaing and his team were able to report that we are not all equal when it comes to emulsifiers. Some people, deemed to be emulsifier-sensitive, have a microbiota that is highly reactive to them, whereas others appear to have a microbiota that is completely resistant to their negative effects. Given the omnipresence of this class of food additives in our modern diet, it has become necessary to better understand these variations in sensitivity between individuals, in order to promote better gut and metabolic health.

With this goal in mind, Chassaing’s team has succeeded in predicting a given person’s sensitivity to an emulsifier, by performing an in-depth analysis of their microbiota.

To do this, the researchers developed a laboratory microbiota modelling system capable of reproducing the human microbiota. This model enabled the researchers to test the effect of CMC on different microbiotas in vitro, leading to the observation that a given microbiota can either be sensitive or resistant to CMC. In addition, it was possible to perfectly validate the predicted sensitivity of a given microbiota thanks to microbiota transfer approaches in a mouse model, with the observation that only those microbiotas predicted to be sensitive to emulsifiers were in fact able to lead to severe colitis in animals consuming CMC.

Using stool samples, the researchers then identified a specific metagenomic signature (analysis of the bacterial DNA contained in our intestinal microbiota) of  sensitivity to CMC, making it possible to predict perfectly, by means of simple molecular analyses, whether a given microbiota is sensitive or resistant to this emulsifier.

‘These discoveries could be used in the near future to determine someone’s sensitivity to emulsifiers, in order to offer everyone a suitable nutritional programme, explains Chassaing, leader of an Inserm research team at Institut Pasteur and last author of the study.

‘Detecting this sensitivity in healthy people could also help prevent the onset of various intestinal disorders – and in patients, prevent the progression of the disease and/or reduce its symptoms.’

The scientists will now use a much larger cohort of patients with Crohn’s disease to validate these predictive approaches of emulsifier sensitivity. They will also now try to explain the molecular reasons for this sensitivity to emulsifiers, and identify approaches aimed at beneficially manipulating the intestinal microbiota to protect it against emulsifier-mediated inflammation.

[1]On processed products, CMC is also referred to as E466.

Colorized transmission electron micrograph of mpox virus particles (orange) found within an infected cell (brown), cultured in the laboratory. Image captured at the NIAID Integrated Research Facility (IRF) in Fort Detrick, Maryland. © NIAID

Central Africa, especially the Democratic Republic of the Congo (DRC), is highly affected by successive mpox outbreaks. Until now, the extent of genetic diversity of the virus had not been well characterised in this region of the world. For the first time, as part of the AFROSCREEN project[1] and the PANAFPOX project[2], teams from the Institut National de Recherche Biomédicale (INRB) in DRC, IRD and Inserm have provided important new information on the genetic diversity of mpox virus circulating in DRC and on the predominant route of transmission. Results of this work have just been published on the Cell website on 24 October 2024.  

Mpox is a viral zoonosis most likely transmitted from rodents to humans. The first case was reported in the Democratic Republic of the Congo (DRC) in 1970. This disease, which had been endemic mainly in rural and forested areas of West and Central Africa for several decades, spread around the world in 2022, including cases in European countries. For the first time, the disease has spread rapidly between individuals through sexual contact, a mode of transmission rarely observed before. This growing mpox outbreak has led to a declaration of a public health emergency of international concern.

The mpox virus can be divided into two major clades*. Clade I, the ‘historical’ strain of the virus, found in the Congo Basin and Central Africa, and clade II, present in West Africa, with clade IIb, found in Nigeria and responsible for the 2022 mpox outbreak.

The most affected country is DRC, where the number of cases has doubled in recent years, rising from around 3,000 in 2021 to 5,600 in 2022, and from over 14,000 in 2023 to over 20,000 by 1^st September 2024. This increase is accompanied by an alarming expansion of the geographical spread, first in eastern DRC but also in urban areas including the capital city Kinshasa, and in neighbouring countries (Rwanda, Burundi, Kenya and Uganda) previously unaffected by mpox. On 14 August 2024, the substantial rise in mpox cases led the World Health Organisation to declare the mpox outbreak a public health emergency of international concern for the second time. These new infections have been attributed to clade Ib, a new variant of clade I with increased numbers of APOBEC3** mutations, which indicate that the virus has adapted to human hosts.

The study, conducted in DRC between February 2018 and March 2024, aimed to investigate whether the rising numbers of mpox infections in the country were due to zoonotic spillovers or viral evolution linked to human adaptation and sustained human-to-human transmission. A total of of 337 viral genomes from 14 out of 26 provinces were successfully sequenced. All new sequences from the South Kivu province, in eastern RDC, corresponded to the recently described clade Ib. This variant is associated with sexual contact and sustained human-to-human transmission, and the limited genetic diversity is compatible with its emergence in 2023. All other genomes from other provinces (i.e. 95% of cases) belonged to clade Ia, which is characterised by high genetic diversity and a low number of APOBEC3 mutations compared with clade Ib. The study results therefore suggest a predominance of zoonotic transmission of mpox in the human population. The co-circulation of genetically diverse viral lineages in small geographical areas even suggests multiple zoonotic introductions over a short period from one or more reservoir species.

For the first time, a large number of clade I mpox sequences have been analysed. This study has provided important new information about the genetic diversity of mpox viruses circulating in DRC, and shows that there are two modes of transmission: zoonotic transmission (clade Ia), which predominates, and human-to-human transmission, which is emerging (clade Ib) in South Kivu and is spreading rapidly to other regions in DRC and neighbouring countries. The presence of several clade I variants in urban areas, particularly Kinshasa, also highlights the need to continue monitoring the evolution and diversity of the virus in DRC as well as its modes of transmission. It is also urgent to better document the animal reservoirs involved in zoonotic transmission.

* a group of organisms,incliuding a particular organism and all of its descendants.

** APOBEC3 (Apolipoprotein B Editing Complex) are proteins that help protect against viral infections.

[1] Project coordinated by ANRS MIE in partnership with IRD and the Institut Pasteur, and financed by the French Development Agency (AFD).

[2] Multidisciplinary project with a “One Health” approach, funded by ANRS MIE.

In this work, scientists analyzed cellular immunity in 230 participants in Guinea © Aurélie Wiedemann

Epidemics of Ebola virus disease occur periodically in several sub-Saharan African countries. Two vaccines have already received WHO prequalification[1] against the Ebolavirus Zaire species. However, information on the long-term immune response to these vaccines is still insufficient. We need to consolidate our knowledge on this subject to continue developing the safest and most effective vaccination strategies possible, for both adults and children. In a new study conducted in Guinea, scientists from VRI, Inserm and Université Paris-Est Créteil (U955 Institut Mondor de recherche biomédicale)[2] have taken a further step in this direction. They have shown that the cellular immune response induced by three different vaccine strategies is maintained for up to five years after vaccination. These results, which support current vaccine strategies against Ebola, are published in Nature Communications.

The Ebola virus causes high fevers and hemorrhages, often resulting in death. Many countries in sub-Saharan Africa regularly face epidemic outbreaks.  the Ebola virus caused the largest epidemic known to date in West Africa in 2014. It has since re-emerged several times in the DRC, but also in Guinea. Vaccination is today one of the most effective tools for combating the disease, and one of the major challenges for research and public health strategy is to continue improving knowledge of the immune response induced in the long term by currently available vaccines.

Since 2019, two vaccines have obtained WHO prequalification against the Ebolavirus Zaire strain: the rVSVΔG-ZEBOV-GP vaccine (Ervebo®), developed by Merck, Sharpe & Dohme, Corp. and the vaccine regimen comprising Johnson & Johnson’s Ad26.ZEBOV (Zabdeno®) vaccine and Bavarian Nordic’s MVA-BN-Filo (Mvabea®) vaccine.

In 2022, the international PREVAC consortium (see box at the end), comprising Inserm, NIH and the London School of Hygiene and Tropical Medicine (LSHTM), published a study in the New England Journal of Medicine examining the safety and efficacy of three vaccine regimens:

• The first vaccine regimen tested consisted of one dose of Ad26.ZEBOV vaccine, followed 56 days later by one dose of MVA-BN-Filo;
• The second regimen involved a dose of rVSVΔG-ZEBOV-GP;
• Finally, the third schedule began with a dose of rVSVΔG-ZEBOV-GP, followed 56 days later by a booster dose of the same vaccine.

Published results showed a high serum antibody response  12 months after vaccination. However, it was essential to obtain information on the long-term maintenance of the response, and in particular regarding the cellular response (see box below).

In December 2023, the 5-year follow-up of participants in the PREVAC clinical trial was completed. The results are being analyzed and will enable assessment of long-term immunity. sIn an ancillary study, scientists analyzed cellular immunity in 230 participants in Guinea, just after vaccination, at one year and five years post-vaccination.

“This is the first study from the PREVAC consortium to look specifically at participants’ cellular immune response. It completes the knowledge already acquired on the humoral response at one year and offers the first follow-up results at 5 years”, emphasizes Aurélie Wiedemann, immunologist at VRI and the Institut Mondor de recherche biomédicale (Inserm/Université Paris Est Créteil) and first author of the study.

Using blood samples taken in Conakry, the scientists were able to analyze the response of CD4+ and CD8+ T lymphocytes to vaccination. They showed the presence of anti-Ebola CD4+ T cells five years after vaccination, regardless of the vaccination regimen. The persistence of these responses is important for the maintenance of humoral immune memory in the event of exposure to the Ebola virus. In a subgroup of volunteers, the authors show a correlation between CD4+ T cell response and the quantity of specific antibodies in the long term.

While CD4+ T response is important for maintaining an antibody response, the presence of cytotoxic CD8+ T cells is also crucial for effective antiviral protection. A specific CD8+ T cell response was demonstrated in individuals vaccinated with two of the three vaccine regimens.

“These results will shortly be supplemented by humoral response data – on antibody production – from all PREVAC consortium countries, on a larger number of participants. Nevertheless, these results are promising and suggest that vaccination against the Ebola virus can induce long lasting immunity. They also pave the way for adjusting current vaccination strategies, by making it possible to assess, for example, the need for a long-term booster vaccination”, explains Prof. Yves Lévy, Director of the VRI and final author of the study.

In 2020, the team also published a study in Nature Communications on the immunity of Ebola survivors two years after discharge from hospital. One of the next avenues of research could be to compare the long-term immune response of these survivors with that induced by vaccination, in order to identify possible correlates of protection [1] against infection, as these are currently undetermined.

Thus, this new study could help identify vaccine responses that would be effective against the infection, improve current vaccine strategies, and define long-term booster vaccine strategies to maintain protection for particularly at-risk individuals such as healthcare workers in Africa.

[1] Prequalification means that a vaccine meets WHO standards of quality, safety and efficacy. On the basis of this recommendation, UN agencies and the Gavi Alliance can purchase the vaccine for at-risk countries.

[2] This analysis was carried out in collaboration with the SISTM team at the Bordeaux Population Health Research Center (UMR 1219 Université de Bordeaux/Inserm).

[3]  These are immunological markers associated with protection against infection: for example, post-vaccination antibody levels against hepatitis B are a good correlate of protection. In other words, in the context of vaccination, they designate the parameters that scientists monitor to find out whether the vaccine works and protects effectively against infection.

Presence of hepcidin (in brown) in the epidermis of a patient with pustular psoriasis. © Élise Abboud

Psoriasis is a chronic inflammatory disease characterised by the rapid and excessive multiplication of skin cells. Although research is progressing and certain treatments are already able to improve the daily lives of patients, this disease remains incurable. The team led by Carole Peyssonnaux, Inserm Research Director at Institut Cochin (Inserm/CNRS/Université Paris Cité) has shown that a hormone that regulates iron in the body, called hepcidin, is produced by the patients’ skin and is essential for triggering psoriasis. This discovery opens up new avenues for treatment. Drugs that block the action of hepcidin could be a therapeutic alternative in psoriasis. These findings have been published in Nature Communications.

Psoriasis is a chronic inflammatory disease that primarily affects the skin. It is common and affects 2 to 3% of the world’s population. Despite many treatment options available to improve patient care, psoriasis remains a chronic condition with no definitive cure.

Characterised by red patches covered with scales, the disease manifests as an excessive proliferation of epidermal cells and an excess of immune cells in the skin, accompanied by a local inflammatory reaction.

Over the last few decades, much progress has been made in understanding the disease, such as the identification of certain genetic factors. Several studies, whose findings are still little known by the scientific community, have also shown that there is an accumulation of iron in the skin of psoriasis patients. We know that the regulation of iron levels in the body is controlled by a hormone called hepcidin. While hepcidin is primarily synthesised by the liver, it can be produced by other organs or tissues under disease conditions.

For years, the Iron and Immunity team at Institut Cochin, led by Inserm Research Director Carole Peyssonnaux, has studied hepcidin closely. Despite the proven presence of iron in the epidermis of psoriasis patients, the production by the skin and the potential role of this ‘iron hormone’ in psoriasis had never been investigated. The researchers therefore decided to study this avenue more closely.

The team[1] started by showing that hepcidin was expressed in the skin of patients with psoriasis, particularly in severe forms such as pustular psoriasis, which is characterised by the accumulation of a type of white blood cell – neutrophils – within the epidermis.

To further study the role of hepcidin in psoriasis, the team then developed new mouse models in which the hepcidin gene was specifically inactivated or overexpressed in the epidermis. The scientists then showed that when this gene was activated, certain characteristics of psoriasis were induced, including skin lesions and the recruitment of neutrophils in the epidermis. Conversely, when the gene was inactivated, the psoriasis markers disappeared.

‘Hepcidin plays a key role in the development of psoriasis. Based on our findings, we show that when psoriasis is triggered, the hepcidin produced by the epidermis plays a crucial role in retaining iron in the skin cells. With iron being an essential metal for cell proliferation, this retention promotes cell division in the epidermis of “psoriatic” skin. What is more, hepcidin-mediated iron retention also contributes to the recruitment of neutrophils, another characteristic of psoriatic skin lesions, particularly pustular’, explains Peyssonnaux.

The next step would be to explore these findings in greater depth, with the goal of developing drugs to block the action of hepcidin and therefore potentially benefit patients with psoriasis, particularly those suffering from an acute and resistant form. With this in mind, the team is developing, with the support of Inserm Transfert[2], new drugs capable of neutralising hepcidin, in order to test them in animal models of psoriasis.

‘In the future, if our findings prove conclusive, such drugs could be used as maintenance therapy following a flare-up, during phases of remission, to prevent recurrence of the disease. Additional studies will determine whether hepcidin also plays a role in other inflammatory skin diseases’, concludes Peyssonnaux.

[1]In collaboration with the team of Selim Aractingi (Cochin Hospital) and Hervé Bachelez (Saint-Louis Hospital)

[2] Patent WO2016/146587 / EP3268027B1 and US11203753B2