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

Vaccination © Inserm/Depardieu, Michel

The ANRS DOXYVAC trial, promoted and funded by ANRS Emerging Infectious Diseases, and conducted by research teams from Inserm, AP-HP, Université Paris Cité and Sorbonne Université (France), shows that a rapid rollout of smallpox vaccination with MVA-BN (Modified vaccine Ankara) among HIV-positive men who have sex with men significantly reduces the risk of mpox by 99%. The results of this study were published in The Lancet Regional Health-Europe on 31 July 2024.

In May 2022, cases of mpox, formerly known as monkeypox, were reported in more than 100 countries where the disease was not endemic. In France, the first case was reported on 19 May, with a rapid increase in infections among men who have sex with men (MSM).

The ANRS DOXYVAC trial, which began in 2021, was designed to study how to improve protection against sexually transmitted infections (STIs) in HIV-positive men who have sex with men.* So, when it became apparent during the course of the study that mpox cases could occur in the trial population, a smallpox vaccination was conducted, as soon as preventive  vaccination in multi-partner MSM was recommended  by French Health Authorities (HAS) on 11 July 2022.

To date, there is no specific vaccine against mpox. However, the virus is closely related to that of human smallpox, and the smallpox vaccine has been shown to be more than 95% effective in protecting against mpox. The vaccine used in the trial, Imvanex® (MVA-BN: Modified vaccine Ankara) from Bavarian Nordic, is a third-generation vaccine. This type of vaccine is produced from smallpox virus with the same antigens as historical smallpox. More specifically, it contains a highly attenuated form of the vaccinia virus known as “modified vaccinia virus Ankara”, a virus that does not cause disease in humans and cannot reproduce in the cells of people who are vaccinated. This means that the vaccine cannot cause local or systemic infections, particularly in immunocompromised people (such as those infected with HIV).

The aim of the analysis among participants of the ANRS DOXYVAC trial was to assess the incidence of mpox infection in participants before (9 May-10 July 2022) and after the launch of the MVA-BN vaccination campaign (from 11 July 2022), and to study the respective effects of vaccination and sexual behaviour adopted during the epidemic period on changes in incidence.

Of the 472 participants included in the analysis, 20% had been vaccinated against smallpox in childhood. The incidence rate** of mpox among trial participants, all of whom were on HIV pre-exposure prophylaxis (PrEP) and had a history of bacterial STIs, was high (49.3 per 1,000 participant-months between 9 May and 20 September 2022).

Vaccination implementation was rapid: 86% (341/398) of eligible participants had received at least one dose of MVA-BN vaccine by 20 September 2022. People were also particularly receptive to the prevention messages and recommendations, especially those with more than ten sexual partners in the last three months who are most at risk. Their sexual behaviour changed significantly before and after 9 May, leading to a reduction in the proportion of people with more than 10 partners in the last 3 months (45% compared with 38%). A significant reduction in the incidence rate of mpox was observed between the period prior to vaccination (67.4 per 1,000 months between May 9 and July 10, 2022) and the period following the launch of the vaccination campaign (24.4 per 1,000 months between July 11 and September 20, 2022).

This trial demonstrated that the rapid implementation of smallpox vaccination with MVA-BN in MSM undergoing PreP significantly reduced the risk of mpox, with an estimated 99% reduction in incidence between the two periods. The reduction in risky sexual behaviour among those most at risk also probably contributed to the reduction in incidence, but to a lesser extent than the vaccination programme.

This study emphasises that identifying and prioritising at-risk populations, delivering targeted prevention messages and awareness campaigns, ensuring the availability of a smallpox vaccine and, above all, the rapid rollout of vaccination to people at risk should enable health authorities to control a future mpox epidemic like the one that occurred in 2022.

* DOXYVAC has demonstrated the efficacy of post-exposure doxycycline in reducing the occurrence of chlamydial infections, syphilis and, to a lesser extent, gonococcal infections.

** Incidence is the number of new cases of a disease in a year in a given population (not to be confused with prevalence, which refers to the number of sick people at a given time). The incidence rate of a disease corresponds to the number of individuals having contracted a disease per 1,000 people exposed to the risk of this disease (in the DOXYVAC trial, it is calculated for one month) (https://www.ined.fr/en/glossary/incidence-of-a-disease/).

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.

Microscopic 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).

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 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.