Publication of Explore Covid-19 translationnal study findings

Coronavirus SARS-CoV-2 causing COVID-19 disease observed in close-up on the surface of a human respiratory epithelial cell.©M.Rosa-Calatrava/O.Terrier/A.Pizzorno/E.Errazuriz-cerda

New research suggests targeting C5a-C5aR1 axis could limit severe inflammatory response

Innate Pharma SA (Euronext Paris: IPH – ISIN: FR0010331421; Nasdaq: IPHA) (“Innate” or the “Company”) today announced the publication of a Nature paper entitled, “Association of COVID-19 inflammation with activation of the C5a-C5aR1 axis,” authored by Innate researchers in partnership with scientists from Hôpitaux Universitaires de Marseille AP-HM (La Timone and North Hospitals), Laveran Hospital, Aix Marseille University, the Centre d’Immunologie de Marseille-Luminy (Inserm, CNRS, AMU) and Marseille Immunopole/AP-HM immunoprofiling laboratory at La Timone Hospital. 

This Marseille-based exploratory research taskforce, named EXPLORE COVID-19, analyzed immune cells in COVID-19 patients at different stages of the disease. The goal of the study was to gain translational insights to better understand the immune response in COVID-19 patients and identify potential targets to fight the viral infection.

The study found that patients who progress towards severe COVID-19 disease, including those with severe pneumonia and acute respiratory distress syndrome (ARDS), exhibit an activation of the C5a/C5aR1 pathway. Specifically, researchers observed high levels of circulating C5a and over-activation of the C5a-dependent myeloid cell pathway, which is believed to contribute to inflammation in the lungs.

This research also focused on avdoralimab (IPH5401), a clinical-stage monoclonal antibody that blocks C5aR1 (CD88). Avdoralimab prevents C5a-induced myeloid cell recruitment and activation. Innate is currently investigating avdoralimab in oncology, which provided pharmacokinetic and safety data prior to investigation in COVID-19.

The findings published in Nature suggest that the C5a-C5aR1 axis blockade could be considered as a potential therapeutic strategy for severe respiratory disease associated with SARS-Cov-2 infection. The analysis found the C5a-C5aR1 axis blockade as a means of limiting myeloid cell infiltration at inflammatory sites and preventing the excessive lung inflammation associated with ARDS in COVID-19 patients.


“There is an urgent need to better understand COVID-19 disease progression and the associated complement cascade to help improve the prognosis of COVID-19 patients who present severe symptoms,” said Pr. Eric Vivier, PhD, Chief Scientific Officer at Innate Pharma and Professor at AP-HM, Aix-Marseille University and Centre d’Immunologie de Marseille-Luminy (Inserm/CNRS/AMU). “We are encouraged by this exploratory study, as we’re beginning to understand the impact of the immune response on the evolution of COVID-19 and pathways able to modulate this response.”    


Based on findings from this study, the Company previously announced the launch of an investigator-sponsored trial named FORCE (FOR COVID-19 Elimination). This is a randomized, double-blind Phase II clinical trial to further explore avdoralimab in COVID-19 patients with severe pneumonia, which is currently ongoing.


You can read the full publication in Nature here.


About the EXPLORE COVID-19 study:

Researchers analyzed the immune response of COVID-19 patients with no or few symptoms, patients who require oxygen, and a group of severe patients who require prolonged mechanical ventilation. The study included 82 individuals: 10 healthy controls and 72 COVID-19 patients, including 10 patients presenting few symptoms, 34 patients with pneumonia, and 28 patients with ARDS.

Avdoralimab in cancer:

Avdoralimab is a therapeutic antibody that specifically binds and blocks C5a receptor 1 (C5aR1) expressed on myeloid cells, including monocytes, macrophages and neutrophils.  It is currently in Phase I development in solid tumors, including hepatocellular carcinoma and non-small cell lung cancer.  

Avdoralimab in COVID-19:

C5a has been implicated in the pathogenesis of ARDS by promoting a proinflammatory environment, through the attraction of myeloid cells (neutrophils, monocytes and macrophages) and the stimulation of their cytokines production. Avdoralimab blocks C5aR1 and has the potential to reduce the inflammatory response in the lungs.

The increased reproductive rate of the virus heralding a second wave, really?

Adobe Stock

While the virus is still circulating throughout the country with 610 clusters detected since 9 May 2020 according to the Directorate General for Health (DGS), fears of a “second wave” are growing. In order to better understand the epidemic dynamics, several indicators are taken into account by epidemiologists and health authorities.

One of them, the reproduction rate of the R virus, is particularly studied because it provides valuable information on an important aspect of the epidemic: the transmissibility of the virus.

However, it cannot be interpreted in isolation to predict a possible resurgence of the epidemic, and must be analysed carefully in the light of other indicators of the health situation and linked to available epidemiological data. A reproduction rate greater than 1 cannot by itself be a precursor of a second wave.

What is the reproduction rate R?

The reproduction rate is an estimate (over the last 7 days) of the average number of people that a carrier of the virus infects. It is calculated from three parameters: the probability of transmission of the virus during a risky contact, the number of risky contacts and the duration of the generation interval between two infections (which can be assimilated to the duration of the contagious period).

For example, in France, on 15 March 2020 (shortly before the epidemic peak), the R was estimated to be 2.8 (i.e. a carrier of the virus infected an average of 2.8 people). It then decreased during the lockdown period, mainly due to the reduction in the number of at-risk contacts between people. For example, on May 11, 2020, when deconfinement was implemented, it was 0.8. In other words, an infected person was infecting less than one other person. Based in particular on these figures, the epidemic was then considered to be on the decline in France.

For several weeks now, the reproduction rate has been increasing. On 24 July 2020, the national reproduction rate had thus reached 1.3. Nevertheless, significant regional variations were noted (the most affected region being currently Brittany with an R equal to 1.87).

These figures reflect a rebound in the epidemic, but the R remains a volatile indicator, particularly sensitive to variations in the number of cases, even when these are small. For example, in the context of massive testing campaigns, it can rapidly increase because a large number of cases is suddenly detected.

Get a more complete picture

To better understand the resurgence of the epidemic, it is also necessary to look at other indicators transmitted by the DGS which, beyond the transmissibility of the virus, also reflect the severity of the health situation and provide additional information on the risk of a second wave.

Among them, the positivity rate of RT-PCR tests carried out. As of 24 July, it was 1.2%, a slight increase over the past three weeks. To this indicator should be added the incidence rate, which is an estimate of the number of new cases of Covid-19 diagnosed by RT-PCR tests, in relation to the number of inhabitants in each department.

Equally important for estimating the threat of a “second wave” and proposing optimal management of the epidemic, it is also important to understand the risk to the hospital system. This is why, among the indicators of epidemic recovery, the health authorities are interested in hospital tensions on beds in intensive care units. A figure which today reaches 8.9% and which corresponds to the average occupancy rate of beds in intensive care units by Covid-19 patients compared to the initial capacity of intensive care beds by region.

To go further, other elements also remain under surveillance, for example the presence of clusters (127 under investigation as of 24 July), tensions on supplies (equipment, medicines, etc.), or particular situations impacting the epidemic at a local level (epidemic co-circulation, social climate, population displacements, etc.). The analysis of all these indicators must be carried out in collaboration with actors in the field who are familiar with the situation in their locality.

The idea is to understand the dynamics of the epidemic as accurately and comprehensively as possible. Always with one objective: to limit the circulation of the virus and the number of cases on the territory, to preserve the health system, and to offer the best possible care to all patients.

Text written with the support of Inserm researchers Vittoria Colizza and Dominique Costagliola (Pierre-Louis Institute of Epidemiology and Public Health).

COVID-19: Together, Remdesivir and Diltiazem Open up New Therapeutic Avenues

SARS-CoV-2 infected human respiratory epithelium. The image shows viral clusters in the cilia of the epithelial cells, numerous highly-characteristic cytoplasmic vesicles containing large electron-dense accumulations of viral material, and numerous viruses being formed. © Manuel Rosa-Calatrava, Inserm; Olivier Terrier, CNRS; Andrés Pizzorno, Signia Therapeutics; Elisabeth Errazuriz-Cerda, UCBL1 CIQLE. VirPath (International Research Center for Infectious Diseases U1111 INSERM – JRU 5308 CNRS – ENS Lyon – UCBL1). Colorized by Noa Rosa C.


As the COVID-19 pandemic continues, finding a treatment to effectively combat the disease remains a major research challenge. Researchers from Inserm, CNRS, Université Claude Bernard Lyon 1 and ENS Lyon at the International Research Center for Infectious Diseases have developed a unique strategy for selecting, evaluating and repurposing existing drugs to assess their efficacy against SARS-CoV-2. They have also developed several highly-relevant preclinical models of infection using human respiratory epithelia of nasal and bronchial origin reconstituted in vitro. Thanks to their expertise, the researchers show that combining the Ebola treatment remdesivir with the antihypertensive diltiazem could bring significant benefit to COVID-19 patients. Their findings have been published in Cell Reports Medicine.

As part of the REACTing program coordinated by Inserm, the VirPath team led by Inserm researcher Manuel Rosa-Calatrava at the International Research Center for Infectious Diseases (Inserm/CNRS/Université Claude Bernard Lyon 1/ENS Lyon) is working on repurposing existing drugs for new therapeutic indications in viral infections.

To test the therapeutic efficacy of these molecules against COVID-19, the team began developing and characterizing experimental models of viral infection in February. This involved the in vitro reconstitution – as close as possible to human physiology – of human respiratory epithelia of nasal and bronchial origin. “We have been using these preclinical infection models, which are highly predictive of in vivo infection, for several years,” clarifies Rosa-Calatrava.

The researchers have also developed protocols for viral-genome and infectious-particle quantification. Their observations and analyses confirm and supplement current knowledge of the mechanisms of SARS-CoV-2 infection and virus-host interactions. “One particular observation from our models infected with the virus was the induced production of interleukin IL6, which is a marker of the disease’s severity,says Rosa-Calatrava.

A large number of drug candidates were evaluated using these models, including two molecules of interest: remdesivir and diltiazem, alone and in combination. Remdesivir presents antiviral activity against RNA viruses, including SARS-CoV-2. In vitro cell models, animal models, as well as several ongoing clinical trials are showing initial positive results against this virus.

Diltiazem is an antihypertensive used in the treatment of angina pectoris. It has already been characterized and repurposed by VirPath researchers to strongly stimulate the endogenous antiviral innate immune response, particularly against influenza- and respiratory viruses. The human toxicity of these two repurposed molecules has also already been evaluated, significantly reducing the time needed for their clinical development in the new SARS-CoV-2 indication.

The results of this study show a significant reduction in viral load in SARS-CoV-2 infected epithelia when treated with remdesivir. This effect is increased when diltiazem is added in combination. “By stimulating the innate immune response of the epithelia, diltiazem potentiates the effect of remdesivir and makes it possible to reduce doses. This bearing in mind that remdesivir presents some in vivo toxicity in addition to being a very costly drug,” emphasizes Rosa-Calatrava.

The team is continuing its preclinical tests with this dual therapy in animal models and hopes to launch a clinical trial as early as next winter if the positive results are confirmed.

Ebola Survivors Present Severe Immune System Abnormalities Two Years After Recovery

This study is the fruit of close collaboration between teams from Inserm, IRD, INSP, Université Paris-Est Créteil, and CERFIG in Guinea. © Aurélie Wiedemann.


Four years after the end of the Ebola epidemic in West Africa, and as it continues to wreak havoc in the Democratic Republic of Congo, the scientific community wonders about the after-effects that may remain among survivors. To learn more, researchers from Inserm and Université Paris-Est Créteil at the Institute for Vaccine Research decided to look at how their immune profiles had changed. To do this, they studied a cohort of survivors developed by Inserm, the French National Research Institute for Sustainable Development (IRD) and the Center for Training and Research in Infectious Diseases in Guinea (CERFIG) – the PostEboGui cohort. Their findings reveal the presence of abnormal levels of immune and inflammatory markers in the blood two years after developing the disease. These have been published in Nature Communications.

In the 2013-2016 Ebola outbreak in West Africa, more than 28,000 people were infected, causing over 11,000 deaths. While the long-term health impacts on survivors are still poorly understood, an increasing number of studies describe persistent clinical after-effects in these patients, such as generalized fatigue, musculoskeletal pain, and eye disorders.

To pinpoint these health problems, the research teams used data from the follow-up of cohorts of survivors, such as the Inserm PostEboGui cohort, developed with the French National Research Institute for Sustainable Development (IRD) and the Center for Training and Research in Infectious Diseases in Guinea (CERFIG). Made up of 802 former Ebola patients enrolled in several centers across Guinea, the aim of this cohort was to describe and analyze the clinical, immunological, psychological and socio-anthropological impacts of Ebola over a two-year period.

The study, published in Nature Communications and conducted by Prof. Yves Lévy with Aurélie Wiedemann at the Vaccine Research Institute (VRI, Inserm/Université Paris-Est Créteil), is one of the first to focus on the long-term immuno-inflammatory profile of Ebola survivors.

The researchers based their study on the analysis of blood samples from 35 members of the PostEboGui cohort who were recruited to participate in this study on average two years after the onset of their disease. A control group was also set up to compare their immune profiles. Each patient was seen three times for these blood samples to be taken. Samples of saliva, urine and semen were also analyzed in order to rule out the presence of the virus.

Such research was only possible thanks to the involvement of the local teams, which had been specifically trained in handling biological samples. It is therefore the fruit of close collaboration between Inserm and IRD teams and Guinean laboratory technicians and scientists at the National Institute of Public Health (INSP) and CERFIG.

Inflammation and immune markers

Analysis of the blood samples showed that even when survivors are physically recovered and no longer have any detectable virus, they still present a specific immune profile, different from that of people who have never contracted the disease.

In particular, the researchers identified the presence of immune cells known as CD4+ and CD8+ memory T cells, specific to the virus, which remained in the blood of the 35 survivors two years after the disease. In addition, there was also a higher number of cytotoxic CD8+ T cells involved in the destruction of the infected cells as well as the presence of IgG antibodies specific to the Ebola virus in these survivors.

What is more, the team showed the presence of a large amount of inflammatory markers in the blood samples (pro-inflammatory cytokines, markers of immune activation), which indicate the persistence of inflammation in Ebola survivors. Finally, this study showed that certain specific immune markers were associated with the persistence of symptoms in these patients.

These findings therefore highlight the long-term persistence of Ebola-specific immune activity and intense and chronic inflammation in these former patients, two years after being infected with the virus. “Our work underscores the importance of long-term follow-up of Ebola survivors, something that has already been emphasized in studies of clinical after-effects. It is important to see how their condition and immune profile evolve and whether they are moving towards a chronic disease,” says Wiedemann.

In the context of the ongoing Ebola epidemic in the Democratic Republic of Congo, a new cohort with an immunity component is currently being developed there, following a similar strategy to that used to implement PostEboGui. It will be an opportunity for researchers to confirm their findings on the immune profile of survivors in a larger number of patients.

A New Method for Unlocking the Mysteries of Life

To better characterize molecular interactions, researchers must also look at molecular chirality. © Valérie Gabelica

Understanding the three-dimensional structure of DNA and RNA and how they interact with other molecules is necessary for the advancement of biomedical research and drug development. A team led by Inserm researcher Valérie Gabelica at the Nucleic acids: natural and artificial regulation laboratory (ARNA, Inserm/CNRS/Université de Bordeaux)[1] has developed an innovative method pairing mass spectrometry with circularly polarized light, enabling better characterization of these different molecular interactions. This new technique is described in a study published in the journal Science.

A technique widely used in physics and biology laboratories, and also in forensic science to analyze chemical and biological samples, mass spectrometry measures the masses of each molecule in a sample, thereby providing information on how they interact and associate with each other.

Inserm researcher Valérie Gabelica and her team at the ARNA laboratory (Inserm/CNRS/Université de Bordeaux)1 are studying how short DNA and RNA sequences fold in three dimensions and interact with other molecules. To do this, they use mass spectrometry, which gives them valuable insights into how DNA and RNA associate structurally with proteins or pharmaceutical molecules, for example.

However, to better characterize these molecular interactions, the scientists must also look at molecular chirality. A molecule is said to be “chiral” when its 3D structure cannot be superimposed onto its mirror image. Due to its helical shape, DNA is therefore a chiral molecule.

Determining the chirality of a molecule is important for understanding its biological interactions with DNA and proteins – the molecules of living organisms.

Given that measuring molecular weight provides no information on chirality, the use of another technique, circularly polarized light[2], is necessary to study the 3D structure of molecules.

In a study published in Science, the researcher and her team describe a novel tool for studying chirality and how DNA and molecules assemble: a “2-in-1” method pairing a mass spectrometer and a laser that produces circularly polarized light.

Therapeutic prospects

The use of such a technique could open up new biomedical research avenues, particularly in neurodegenerative diseases, such as Alzheimer’s.

Indeed, several studies have shown that upstream of the protein aggregation process that forms senile plaques in the brain, the proteins form small complexes known as oligomers, which could be even more toxic. Applying the method developed by the researchers would make it possible to improve our understanding of when these oligomers change their 3D structure, in order to explore the role they play in disease exacerbation and plaque formation.

Another practical application is drug development. For example, if the target of a drug is a chiral protein, it is also important to characterize the chirality of the drug in order to find out more about its potential interactions.

“In the 1960s, thalidomide, a drug taken by many pregnant women to reduce nausea, caused severe birth defects in their babies. In fact, one of the images of this molecule in the mirror was anti-nausea, the other was toxic. A more in-depth study of the molecular structure and chirality would have prevented this,” emphasizes Gabelica.

By pushing back hard on the frontiers of mass spectrometry and facilitating the study of molecule chirality, this research is particularly innovative and opens up very broad prospects in the field of biomedical research.


[1] The IECB research support unit (CNRS/Université de Bordeaux/Inserm) also participated in this work.

[2]Light is a wave. It is described by signals that oscillate in space and time: electric and magnetic fields. These two fields have a direction, the magnetic field is perpendicular to the electric field. When light is circularly polarized, the electric field changes orientation along the beam and describes a spiral. The magnetic field is always perpendicular to the electric field

Inserm Launches a Platform Evaluating COVID-19 Vaccine Candidates for the Conduct of Large-Scale Quality Trials

To evaluate the safety and efficacy of potential COVID-19 vaccines, rigorous clinical trials are more necessary than ever. © Adobe Stock


The search is on for a COVID-19 vaccine, with many candidates having already reached the clinical trial stage. The participation of France in such trials is scientifically and strategically imperative in order to guarantee access to a safe and effective vaccine for its population. This is why Inserm, with the support of the REACTing network, Public Health France, the country’s university hospitals, and the French College of Teachers in General Practice, is launching COVIREIVAC. This platform for the clinical evaluation of COVID-19 vaccine candidates will make it possible to test them rigorously and obtain robust data on their safety and ability to induce an immune response (immunogenicity).

Unprecedented in scale, the COVID-19 pandemic has already caused more than 500,000 deaths worldwide. While the number of new cases is slowing in some regions, the virus continues to spread, particularly in the USA and Latin America. In order to stop this, the scientific community is pinning its hopes, first and foremost, on the development of a vaccine. Several months after the identification and genetic sequencing of SARS-CoV-2, the World Health Organization (WHO) has listed over 140 vaccine candidates, seventeen of which are already in clinical development.

In order to assess the safety and efficacy of these potential vaccines, rigorous clinical trials are more necessary than ever.

Founded by Inserm in 2007 and labeled a network of excellence in 2013 by its national infrastructure F-CRIN[1] , the Innovative Clinical Research Network in Vaccinology (I-REIVAC) enjoys extensive clinical vaccine research experience and industry visibility, making it an essential stakeholder in the organization of such trials.

With 24 hospital clinical centers distributed throughout France, it also enables extensive participation of the population in the vaccine trials. On the strength of this legitimacy, this network will serve as the support structure for the COVIREIVAC project, which should enable high-quality clinical evaluation of the various COVID-19 vaccine candidates.

A “one-stop shop” for France

This project is based on the observation that France’s access to the most promising candidates will only be possible by setting up a “one-stop shop” serving industry and academia, in order to evaluate these products, guarantee the feasibility of the clinical trials to the industry stakeholders concerned, and negotiate production and market conditions. This approach involves both the establishment of a “scientific committee” tasked with carrying out scientific and strategic evaluation of the various COVID-19 vaccine candidates, and the development of a national platform for their clinical evaluation.

Chaired by Inserm Research Director and CARE committee member Marie-Paule Kieny, the scientific committee is particularly interested in the characteristics of the vaccine candidates that could provide indications regarding their efficacy, safety and production capacity in order to identify the most relevant products. It is working closely with the new vaccine platform, under the leadership of I-REIVAC coordinator Odile Launay, professor of infectious and tropical diseases at Université de Paris and coordinator of the Cochin Pasteur Clinical Investigation Center (CIC) at Cochin Hospital (AP-HP), to test vaccines in rigorous clinical trials that can include several hundred participants.

With the support of the REACTing network, Public Health France, the university hospitals and the French College of Teachers in General Practice, and in order to increase the capacity of the network to participate in COVID-19 vaccine trials, the aim of the platform will be to build a pool of potential participants and increase the number of centers that can accommodate them.

The monitoring of potential side effects, through close collaboration with networks of primary care doctors and the French medicines agency (ANSM), will also be proposed.

“Confronting the severity of the COVID-19 pandemic means ensuring the widest possible access to future vaccines for the French and European populations. Thanks to an existing vaccine network, the COVIREIVAC project can give France the attractiveness it needs to guarantee active participation in the major vaccine trials and early access to the best vaccine candidates,” says Gilles Bloch, Inserm Chairman and CEO.

In the longer term, the initiative will also provide essential information on the safety of these vaccines and their continued efficacy. Collaboration with other European countries, to extend the initiative and enable larger-scale clinical trials, is also something that is being envisaged.

This project receives financial support from the Ministry of Solidarity and Health and the Ministry of Research and Innovation.


[1] French Clinical Research Infrastructure Network

Huntington’s Disease: Brain Abnormalities Detectable in Embryos

Section of the human brain (cortex). The progenitor cells in magenta are less engaged in neuronal differentiation than those in green © Monia Barnat/Grenoble Institut des Neurosciences/Inserm, Université Grenoble Alpes

Huntington’s disease is a genetic neurological condition that usually manifests in adulthood. Teams of researchers and clinicians from Inserm, Université Grenoble Alpes, Sorbonne Université, CNRS and AP-HP at the Grenoble Institute of Neuroscience and the Brain Institute, have discovered abnormalities in the brains of human embryos that carry the mutation responsible for Huntington’s disease. This research, to be published in Science, looks at the mechanisms of the silent progression of the disease and when and how to treat patients in the future.

Huntington’s is a rare and hereditary genetic disease of the central nervous system, which usually manifests between 30 and 50 years of age in the form of gradually-worsening psychiatric, cognitive and motor disorders. It is caused by a mutation of the gene coding for the huntingtin protein and is transmitted in an “autosomal dominant” manner: inheriting just one copy of the defective gene is enough to develop the condition. Around 18,000 people in France are concerned, of whom 6,000 are already symptomatic and around 12,000 possess the gene carrying the mutation but are asymptomatic.

The teams of Sandrine Humbert, Inserm research director at the Grenoble Institute of Neuroscience (Inserm/Université Grenoble Alpes), and Alexandra Durr, university professor-hospital practitioner at Sorbonne Université, Pitié Salpêtrière hospital – AP-HP, and the Brain Institute (Inserm/Sorbonne Université/CNRS/AP-HP), are interested in the early stages of Huntington’s disease and the long period that precedes the onset of symptoms. In new research published in Science, they looked at when brain abnormalities could develop.

The teams studied the brains of 13-week-old human embryos donated by parents following medical termination of pregnancy. They observed several differences between the embryos that carry the mutation of the gene coding for huntingtin and those that do not.

In the carriers, the pathological huntingtin protein is abnormally localized in the progenitor cells that generate the neurons of the cortex. This mislocalization is linked, among other things, to problems of junction protein localization in these cells and to alterations in the size, density and orientation of the

cilium, an organelle essential to the functioning of these cells. These abnormalities disrupt the “division-differentiation” balance of the progenitor cells, which are derived from a reservoir of dividing cells, some of which differentiate into neurons while the others continue to divide in order to provide new progenitor cells. In the embryos that carry the mutation, these progenitor cells start differentiating more quickly at the expense of the reservoir of dividing cells.

The researchers repeated the experiment with a mouse model of Huntington’s disease at an equivalent stage of embryonic development and found the same abnormalities. This meant they could validate this animal model in order to further explore the early mechanisms of the disease at other stages of embryonic development or after birth.

“This is the first time that abnormalities of brain development have been identified in this disease. Abnormalities which are also relatively large and extensive, although we are not yet able to determine their direct consequences,” clarify Humbert and Durr, who led this research.

But why do the carriers of the mutation show no symptoms until later down the line? “At this stage, our hypothesis is that very early on the brain implements compensatory mechanisms that allow normal functioning. It could be the same in people who carry mutations linked to other types of degeneration, such as Alzheimer’s disease or amyotrophic lateral sclerosis,” specify the researchers.

They will now continue to describe brain development in mouse models of Huntington’s disease, try to understand how these early defects contribute to the adult disease, and how their compensation could be regulated during the silent symptomless period. “This discovery also has important implications for how and when disease-modifying therapies should from now on be considered,” they conclude.

Coupe de cerveau humain (cortex)

Human brain section (cortex). On the left, the nuclei are marked in blue; on the right, the progenitor cells in magenta are less engaged in neuronal differentiation than those in green.

©Monia Barnat/Grenoble Institut des Neurosciences/Inserm, Université Grenoble Alpes

Type 1 Interferon Deficiency: A Blood based Signature for Detecting Patients at Risk of Severe Covid-19

Image de microscopie du Coronavirus SARS-CoV-2 responsables de la maladie COVID-19 accrochés aux cellules épithéliales respiratoires humaines

SARS-Cov-2 coronavirus responsible for COVID-19 disease attached to human respiratory epithelial cells ©M.Rosa-Calatraval/O.Terrier/A.Pizzorno/E.Errazuriz-cerda


Paris, July 16th – Which patients will develop a severe form of Covid-19? This is a key question that needs to be answered to improve the individual management and prognosis of patients. In a study published in Science on July 13, teams from AP-HP, Inserm, Université of Paris, Institut Pasteur and Institut Imagine describe a unique and unexpected immunological phenotype in severe and critical patients, consisting of a severely impaired response of interferon (IFN) type I, associated with a persistent blood viral load and an excessive inflammatory response. These data suggest that IFN type I deficiency in the blood could be a hallmark of severe forms of Covid-19. It also supports the potential value of therapeutic approaches that combine early administration of IFN, with appropriate anti-inflammatory therapy targeting IL-6 or TNF-α, in patients preventing severe disease forms.

Approximately 5% of people with Covid-19 progress to a severe or critical form, including the development of severe pneumonia that progresses to acute respiratory distress syndrome. While these forms sometimes occur early in the course of the disease, clinical observations generally describe a two-stage progression of the disease, beginning with a mild to moderate form, followed by respiratory aggravation 9 to 12 days after the onset of the first symptoms. This sudden progression suggests deregulation of the host inflammatory response. A growing number of indications suggest that this aggravation is caused by a large increase in cytokines. This runaway inflammatory response is correlated with massive infiltration in the lungs of innate immune cells, namely neutrophils and monocytes, creating lung damage and acute respiratory distress syndrome.

By analogy with a genetic disease leading to a similar pulmonary pathology identified at Institut Imagine by the team of Inserm researcher Frédéric Rieux-Laucat, the initial hypothesis assumed excessive production of interferon (IFN) type I, a marker of the response to infections. However, in seriously ill patients, the teams of Darragh Duffy (Dendritic Cell Immunobiology Unit, Institut Pasteur/Inserm), Frédéric Rieux-Laucat (Laboratory of Immunogenetics of Pediatric Autoimmune Diseases at Institut Imagine – Inserm/Université de Paris), Solen Kernéis (Mobile Infectiology Team, AP-HP. Centre – Université of Paris) and Benjamin Terrier (Department of Internal Medicine, AP-HP. Centre – Université of Paris) show that the production and activity of type-I IFN are strongly reduced in the most severe forms of Covid-19.

In addition, there is a persistent blood viral load, indicating poor control of viral replication by the patient’s immune system which leads to an ineffective and pathological inflammatory response.

The inflammation, caused by the transcription factor NF-kB, also leads to increased production and signaling of tumor necrosis factor (TNF)-alpha and the pro-inflammatory cytokine interleukin IL-6.

Distinct type-I IFN responses may be characteristic of each stage of the disease

This low signature of type-I IFN differs from the response induced by other respiratory viruses such as human respiratory syncitial virus or influenza A virus, both of which are characterized by high production of type-I IFN.

The study also showed that low levels of type-I IFN in plasma precede clinical worsening and transfer to intensive care. Levels of circulating Type 1 IFN could even characterize each stage of disease, with the lowest levels observed in the most severe patients. These results suggest that in SARS-CoV-2 infection, the production of type-I IFN is inhibited in the infected host, which could explain the more frequent severe forms in individuals with low production of this cytokine, such as the elderly or those with co-morbidities.

Therefore, type-I IFN deficiency could be a signature of severe forms of COVID-19 and could identify a high-risk population.

These results further suggest that the administration of IFN-alpha/Beta combined with anti-inflammatory therapy targeting IL-6 or TNF-α, or corticosteroids such as dexamethasone, in the most severe patients could be a therapeutic avenue to be evaluated for severe forms of COVID-19.

Having surgery under hypnosis, really?

Hypnosis fascinates by its esoteric, almost magical side. One thinks of the hypnotist who puts the crowds to sleep… But there is a whole other field in which hypnosis is being emulated, that of health. How does medical hypnosis work in practice? Can we really count on it to be operated on? And are we all receptive to this practice? Listen only to our voice… Detox Channel cuts off false information.

Star-Shaped Brain Cells Shed Light on the Link Between Cannabis Use and Sociability

In a culture of neurons, feeder cells and astrocytes (star-shaped cell in the center in red) cohabit. Marking of tubulin in green, actin in red, and nuclei in blue. Researchers have focused on these cells to understand the impact of cannabis use on sociability.©Inserm/Saoudi, Yasmina/Ballet, Sandrine

Cannabis use can lead to behavioral changes, including reduced social interactions in some individuals. To better understand the phenomenon, Inserm researcher Giovanni Marsicano and his team from NeuroCenter Magendie (Inserm/Université de Bordeaux), in collaboration with Juan Bolaños’ team from the University of Salamanca, have identified for the first time in mice the cerebral mechanisms underlying the relationship between cannabis and reduced sociability. Their findings have been published in Nature.

Regular exposure to cannabis may have a harmful impact on sociability. For some consumers, studies show that it may lead to withdrawal and reduced social interactions. However, the brain network and the mechanisms involved in this relationship were unclear until now.

In order to learn more about the subject, a group led by Inserm researcher Giovanni Marsicano at NeuroCenter Magendie (Inserm/Université de Bordeaux)[1] has joined forces with a Spanish team from the University of Salamanca led by Juan Bolaños[2].

More broadly, their work is aimed at improving our knowledge of how cannabinoid receptors (the brain receptors that interact with chemical compounds in cannabis) work.

In their study published in the journal Nature, the researchers show that after exposure to cannabis, behavioral changes related to sociability occur as a result of the activation of specific cannabinoid receptors, located in star-shaped cells of the central nervous system called astrocytes.

Cannabinoid receptors and mitochondria

These findings are the result of almost a decade of hard work. In 2012, Marsicano and his team had made a surprising discovery: cannabinoid receptors are not only present on the cell membrane, as previously believed. Some of these receptors are also located on the membrane of the mitochondria, the intracellular organelles whose role is to provide the cells with the energy they need.

This new study comes after the team has identified cannabinoid receptors located on the membrane of the mitochondria within astrocytes. Among other functions, these cells play a very important role in energy metabolism of the brain. They capture glucose from the blood and metabolize it into lactate, which acts as “food” for neurons. “Given the importance of astrocytes and energy use for brain function, we wanted to understand the role of these specific cannabinoid receptors and the consequences for the brain and behavior when exposed to cannabis,” explains Marsicano.

Researchers then exposed mice to the cannabinoid THC, the main psychoactive compound in cannabis. They observed that persistent activation of mitochondrial cannabinoid receptors located in astrocytes resulted in a cascade of molecular processes leading to dysfunction of glucose metabolism in astrocytes.

As a result, the ability of astrocytes to transform glucose into “food” for neurons was reduced. In the absence of the necessary energy intake, the functioning of neurons was compromised in the animals, with a harmful impact on behavior. In particular, social interactions were decreased for up to 24 hours after exposure to THC.

“Our study is the first to show that the decline in sociability sometimes associated with cannabis use is the result of altered glucose metabolism in the brain. It also opens up new avenues of research to find therapeutic solutions to alleviate some of the behavioral problems resulting from exposure to cannabis. In addition, it reveals the direct impact of astrocyte energy metabolism on behavior,” says Marsicano.

At a time when the debate over therapeutic cannabis is returning to the forefront, the researchers also believe that this type of work is needed to better understand how the body’s various cannabinoid receptors interact with the drug, and whether any of them are particularly associated with harmful effects. Such research would make it possible to ensure the optimal management of patients who might need this type of therapy.

[1] With Arnau Busquets-Garcia (now in Barcelona, Spain) and Etienne Hebert-Chatelain (now in Moncton, Canada)

[2] With Daniel Jimenez-Blasco