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Viagra to prevent transmission of the malaria parasite?

By increasing the stiffness of erythrocytes infected by the causal agent of malaria, Viagra favors their elimination from the blood circulation and may therefore reduce transmission of the parasite from humans to mosquitoes. This astonishing discovery, made by scientists from the CNRS, INSERM, Université Paris Descartes – at the Institut Cochin – and the Institut Pasteur, working in collaboration with a team from the London School of Hygiene and Tropical Medicine, could lead to a treatment to reduce the spread of malaria within a population. Their work is published in PLOS Pathogens on 7 May 2015.

Plasmodium falciparum, the parasite that causes malaria, has a complex developmental cycle that is partially completed in humans and partially in the anopheline mosquito. Treatments for malaria target the asexual forms of this parasite that cause symptoms, but not the sexual forms transmitted from a human to a mosquito when it bites. Eradication of this disease thus necessitates the development of new types of treatments against sexual forms of the parasite in order to block transmission and thus prevent dissemination of the disease within the population.

The sexual forms of the parasite develop in human erythrocytes sequestered in the bone marrow before they are released into the blood. They are then accessible to mosquitoes, which can ingest them when they bite (see the top of the image on page 2). But circulating erythrocytes — whether they are gametocyte-infected or not — are deformable, thus preventing their clearance via the spleen, which constantly filters the blood and only retains stiff, old or abnormal erythrocytes. However, gametocyte-infected erythrocytes can easily pass through the spleen and persist for several days in the blood circulation.

During a new study, the scientists thus sought to stiffen the infected erythrocytes. They showed that the deformability of gametocyte-infected erythrocytes is regulated by a signaling pathway that involves cAMP. When the cAMP molecules accumulate, the erythrocyte becomes stiffer. cAMP is degraded by the enzyme phosphodiesterase, whose action thus promotes erythrocyte deformability.

Using an in vitro model reproducing filtration by the spleen, the scientists were able to identify several pharmacological agents that inhibit phosophodiesterases and can therefore increase the stiffness of infected erythrocytes. One of these agents is sildenafil citrate, better known under its brand name of Viagra. The authors showed that this agent, used at a standard dose, had the potential to increase the stiffness of sexual forms of the parasite and thus favor the elimination of infected erythrocytes by the spleen.schéma en

The deformability of gametocyte-infected erythrocytes, facilitated when the cAMP pathway is inhibited, allows them to circulate freely through the spleen and remain accessible to mosquitoes in the blood circulation (top). The action of Viagra increases the stiffness of infected erythrocytes by activating the cAMP pathway, preventing their passage through the spleen endothelium and clearing the parasites from the blood circulation (bottom). © Catherine Lavazec

This discovery could help find new ways to stop the spread of malaria in a population. 

Modifying the active substance in Viagra to block its erectile effect, or testing similar agents devoid of this adverse effect, could indeed result in a treatment to prevent transmission of the parasite from humans to mosquitoes.

This study involved the teams led by Catherine Lavazec and Gordon Langsley at the Institut Cochin and Institut Pasteur and David Baker’s team at the London School of Hygiene and Tropical Medicine. It received support from the CNRS ATIP-Avenir program, INSERM, the Labex Gr-EX and Parafrap, the Fondation Inkermann and the Bill and Melinda Gates Foundation, in the context of a project in collaboration with Pierre Buffet’s team at Université Pierre et Marie Curie.

Inflammatory bowel disease: a gut bacterium with beneficial properties

Several years ago, INRA researchers in Jouy-en-Josas showed that levels of the gut bacterium Faecalibacterium prausnitzii tended to decline in the human gut at the onset of chronic inflammatory bowel disease (IBD). Is this disappearance of F. prausnitzii one of the causes of inflammation, or is its disappearance a consequence of the disease? Today, the same INRA team, in collaboration with an American team (Berkeley), AgroParisTech, lnserm, AP-HP and UPMC, are answering these questions. Not only do their results show that F. prausnitzii plays an active role in protecting against intestinal inflammation, they also propose explanations regarding mechanisms of action. This research is published in the journal mBio on 21 April 2015.

Seven years ago, researchers at INRA (French National Institute for Agricultural Research) drew the attention of scientists and the public to a specific bacterium found in our gut. This bacterium, Faecalibacterium prausnitzii, is abundant in the gut of healthy humans, but as soon as a chronic inflammatory bowel disease (IBD) occurs, it tends to decline. One nagging question has been raised by the scientific community: is the disappearance of F. prausnitzii one of the causes of inflammation, or is its disappearance a consequence of the disease? In other words, is F. prausnitzii a bacterium that might protect our digestive tract from an inflammatory disease?

To find an answer, the researchers used mice harbouring only two types of bacteria in their digestive tract, in contrast to several billion under normal circumstances. Following a treatment that generates inflammation, the presence of F. prausnitzii on its own protects from the development of intestinal inflammation. This demonstrates the anti-inflammatory potential of F. prausnitzii.

The INRA researchers and their colleagues from Berkeley, in collaboration with AgroParisTech, the French National Institute of Health and Medical Research (Inserm), the Paris public hospitals (AP-HP), and Pierre and Marie Curie University (UPMC), also propose new approaches to explaining how this bacterium could protect us. The presence of this bacterium is actually associated with many anti-inflammatory molecules in the gut and bloodstream of animals. F. prausnitzii may be able to provide protection to our digestive tract by a varied arsenal of metabolic activities. For example, salicylic acid, a precursor in the synthesis of drugs used to treat patients with IBD, is found in the gut of mice carrying F. prausnitzii. The bacteria that we harbour may well play an active role in our health via the same strategies that are used in the medical arena.

[exergue]Once there is intestinal inflammation, the decline in the presence of the bacterium F. prausnitzii therefore aggravates the disease. In order to break this vicious cycle leading to chronic inflammation of the digestive tract, the scientists plan to restore the presence of F. prausnitzii using new food supplements containing the bacterium (probiotics) and/or favouring development of the bacterium (prebiotics). [/exergue]This study, which has added to our fundamental knowledge in the area of microbiology, is also at the interface of new industrial and medical applications.ProbioScanning electron micrographs of F. prausnitzii © MIMA 2 Platform, T. Meylheuc)

New gene therapy success in a rare disease of the immune system: Wiskott-Aldrich syndrome

French teams from CIC Biothérapie (AP-HP/Inserm), from pediatric hematology department of Necker Hospital for Children (AP-HP), led by Marina Cavazzana, Salima Hacein Bey Albina and Alain Fischer and from Genethon led by Anne Galy (Genethon/Inserm UMR-S951), and English teams from UCL Institute of Child Health and Great Ormond Street Hospital in London led by Adrian Thrasher and Bobby Gaspar demonstrated the efficacy of gene therapy treatment for Wiskott-Aldrich Syndrome (WAS). Six children that were treated and followed for at least 9 months had their immune system restored and clinical condition improved. This work, which was published today in the Journal of the American Medical Association (JAMA), was carried out with support from the AFM-Telethon.

Wiskott-Aldrich syndrome is a rare congenital immune and platelet deficiency which is X-linked and has an estimated prevalence of 1/250 000. It is caused by mutations in the gene encoding the WAS protein (WASp) expressed in hematopoietic cells. This disease, which primarily affects boys, causes bleeding, severe and recurrent infections, severe eczema and in some patients autoimmune reactions and the development of cancer. The only treatment available today is bone marrow transplantation, which requires a compatible donor and can itself cause serious complications.

The Phase I / II study, with Genethon as the promoter, was launched in December 2010 and conducted in Paris and London to treat severely ill patients without a compatible donor. This study, which is ongoing, assesses the feasibility and efficacy of gene therapy in this indication. The article published in JAMA reports the results for the first six patients, aged 8 months to 16 years, where the monitoring period allowed assessment of the initial effects of the treatment.

The treatment involves collected blood stem cells carrying the genetic anomaly of patients and corrected them in the laboratory by introducing a healthy WAS gene using a lentiviral vector developed and produced by Genethon. The corrected cells were reinjected into patients who in parallel were treated with chemotherapy to suppress their defective stem cells and autoimmune cells to make room for new corrected cells. After reinjection, these cells were then differentiated into the various cell lines that make up the blood (red and white cells, platelets).

To date treated patients showed significant clinical improvement. Severe eczema and severe infection disappeared in all cases. Arthritis was eliminated in one patient and another saw major improvement in vasculitis of the lower limbs and was able to return to normal physical activity without a wheelchair. However, the rate of corrected platelets varies from one patient to another.

Fulvio Mavilio, Chief Scientific Officer Genethon: “We are all very happy and encouraged by the results of this study. It is the first time that a gene therapy based on genetically modified stem cells is tested in a multicenter, international clinical trial that shows a reproducible and robust therapeutic effect in different centers and different countries. For very rare diseases such as WAS, multicenter clinical trials are the only effective way of proving the safety and efficacy of gene therapy and having it rapidly approuved and made available to all patients. We are following the same approach for other rare and less rare blood diseases.

Frédéric Revah, CEO of Genethon, the laboratory of the AFM-Telethon and the trial sponsor, said “These first results of our clinical trial for the treatment of Wiskott Aldrich syndrome are very encouraging. They illustrate not only the ability of Genethon to carry out the upstream research to develop treatments for these rare and complex diseases, but also to construct and conduct international clinical trials, to produce these advanced therapy products, to work with international teams and to manage the regulatory aspects of the trials in France and abroad. These are skills that we implement for other international trials of gene therapy for rare genetic diseases of the immune system, blood, muscle, vision or liver… We will continue the current study with the objective of providing treatment for patients.

Marina Cavazzana: “The results obtained in this multicenter clinical trial constitute an important therapeutic advance (overhang) because they concern a complex pathology which affects almost all of blood cells with dramatic clinical consequences. After transfer of gene, the patients showed a significant clinical improvement due to the reexpression of the protein WASp in the cells of the immune system. The efficiency of the treatment of such a deficit for which a high level of correction of hematopoietic stem cells is required, indicates that it is from now on justifiable to hope to treat other complex genetic diseases as those affecting red blood cells.

Professor Thrasher says: “This is a very powerful example of how gene therapy can offer highly effective treatment for patients with complex and serious genetic disease. It also excitingly demonstrates the potential for treatment of a large number of other diseases for which existing therapies are either unsatisfactory or unavailable.

What if the severity of our seasonal influenza were related to our genetic background?

While most of us recover from influenza after a week, it can be a very severe disease, and even fatal in rare cases, with no reason for physicians to have expected such an outcome. By analysing the genome of a little girl who contracted a severe form of influenza at the age of two and a half years, researchers at the Laboratory of Human Genetics of Infectious Diseases (a joint French-American international laboratory), which brings together researchers from Inserm, Paris Descartes University, and physicians from the Paris public hospitals (AP-HP; Necker Hospital for Sick Children), working at the Imagine Institute, and from The Rockefeller University in New York, have discovered that she has a genetic mutation, unknown until now, that causes a subtle dysfunction in her immune system. More generally, these results show that genetic mutations could be the root cause of some severe forms of influenza in children, and indicate in any event that immune mechanisms missing in this little girl are needed for protection against this virus in humans. These results are published in the journal Science Express.
Woman coughing and blowing her nose in autumn

©fotolia

Seasonal influenza is an acute viral infection caused by the influenza virus. It is characterised by high fever, headaches, sore muscles, etc. Apart from vaccination, there is no treatment for it other than symptomatic (pain) treatment. In most cases, patients recover after a week, but in more vulnerable people influenza can cause acute respiratory distress, which is potentially fatal.

The main known risk factors for severe forms of influenza are some acquired comorbidities, such as chronic lung disease. However, the cause of most fatal cases remains unexplained, especially in children.

The absence of cases of severe influenza in patients with known acquired immunodeficiencies, which usually increase susceptibility to infections, is also surprising.

Given these different observations, the researchers at Jean-Laurent Cassanova’s and Laurent Abel’s laboratory, in Paris and New York, therefore formulated a hypothesis whereby severe influenza in healthy children might be the result of genetic errors.

To test this hypothesis, they sequenced the entire genome of a 7-year-old child who had contracted a severe form of influenza (influenza A virus strain H1N1), requiring her admission to a paediatric intensive care unit in January 2011, at the age of two and a half years. At the time, she showed no other known pathology that might have suggested greater vulnerability to the virus than that of other children.

This analysis, combined with analysis of her parents’ genomes, made it possible to show that the little girl had inherited a mutated allele of the gene encoding interferon regulatory factor (IRF7) from both of her parents. The latter is a transcription factor known to amplify the production of interferons in response to viral infection in mice and humans.

In contrast to her parents, in whom the mutation of a single allele of the gene is of no consequence, in the little girl, mutation of both alleles of the gene encoding IRF7 has led to its inactivation. The result: failure to produce interferons, disrupting her system of defence against influenza virus infection in a cascading manner.

By carrying out a comprehensive series of experiments on blood cells, particularly dendritic cells, and by generating lung cells from stem cells taken from the young girl, the researchers provided proof that the mutations observed in this little girl explain the development of severe influenza. Furthermore, this discovery demonstrates that interferon amplification dependent on IRF7 expression is needed for protection against influenza virus in humans. They now need to search for mutations in this or other genes in other children recruited following an episode of unexplained severe influenza.

Based on these initial observations, the researchers at Inserm believe that therapeutic strategies based on recombinant interferons, available in the pharmacopoeia, could help to combat severe forms of influenza in children.

This multidisciplinary study required multiple collaborations in Europe and the United States.

Targeting a host receptor instead of the virus: a new experimental approach against hepatitis C virus.

An international collaboration led by Professor Thomas Baumert (Inserm/University of Strasbourg Joint Research Unit 1110, “Institute for Viral and Liver Disease”) has shown that a monoclonal antibody directed specifically against claudin-1, a liver protein essential for infection by the hepatitis C virus (HCV), enables the prevention and treatment of chronic infection by this virus in an animal model. It turns out that this antibody, which was known to inhibit HCV entry and thereby prevent the initiation of infection, can also eliminate infected cells. This discovery, published in a letter in the Nature Biotechnology issue of 23 March 2015, opens the way to developing an approach to hepatitis C that is not only preventive, but therapeutic as well.

Infection with hepatitis C virus (HCV) leads to cirrhosis of the liver and liver cancer, the second leading cause of cancer death in the world. These complications are major indications for liver transplantation, but HCV reinfection of the transplant is a challenge. To date there is no vaccine, and the new treatments developed recently can be accessed by only a minority of patients worldwide because of their high cost. The development of new preventive and therapeutic strategies therefore continues.

The team directed by Prof. Thomas Baumert (Inserm/University of Strasbourg Joint Research Unit 1110, “Institute for Viral and Liver Disease”), in collaboration with international teams, decided to target a liver protein essential for viral infection instead of targeting the virus. They chose claudin-1, a molecule that is important in the initial steps of HCV infection, and involved in cell-cell contacts.

Using mouse models with humanised liver, the researchers show that a monoclonal antibody directed against claudin-1 can prevent HCV infection by blocking the entry of the virus into liver cells. Surprisingly, the researchers also observed that this antibody enables the treatment of chronic HCV infection by inhibiting the activation of intracellular signalling pathways needed by the virus for survival. As a result, the infected cells disappear and are gradually replaced by uninfected cells.

The advantage of this strategy is that it does not need to be combined with an antiviral agent.

 Moreover, by using different viral strains, the researchers show that it is difficult for the virus to escape from this antibody and develop resistance.

“Claudin-1” is a protein that is usually localised in the tight junctions that are the points of contact between adjacent cells. It is interesting to note that tight junction proteins constitute receptors for other pathogens, such as dengue virus and Shigella species. This innovative approach, employing injection of a monoclonal antibody directed against a protein on the host cell, makes it possible to foresee the development of a vaccine strategy and new therapeutic approaches against HCV, and also against other pathogens that use similar infection mechanisms.

This study received support from the European Union (ERC, INTERREG-IV-Upper Rhine [ERDF], FP7), ANRS (French National Agency for Research on AIDS and Viral Hepatitis), the HepSYS and netRNA Laboratories of Excellence of the French National Research Agency (ANR), ARC Foundation for Cancer Research, IHU Strasbourg MIX-Surg, Wilhelm Sander Foundation, Alsace Region, French National Cancer Institute (INCa), French National Institute of Health and Medical Research (Inserm), French National Scientific Research Centre (CNRS), University of Strasbourg, Ghent University (GOA 01G01712), Flanders Research Foundation (FWO) and Cardiex (Nantes).

An antihypertensive drug improves corticosteroid-based skin treatments

Basic research on blood pressure has led researchers from Inserm (Inserm Unit 1138, “Cordeliers Research Centre”) to obtain unexpected results: drugs used to treat hypertension (high blood pressure) reduce side effects from corticosteroid-based creams used to treat certain skin diseases.

This work is published in the Journal of Investigative Dermatology.

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Corticosteroid-based dermatological creams are indicated for the symptomatic treatment of inflammatory skin conditions, such as atopic dermatitis and psoriasis, for example. However, they have frequent side effects, such as a slight burning sensation, and very often end by inducing skin atrophy (thinning of the skin, which becomes fragile), which is inconvenient for the patient, and for which there is presently no treatment.

The researchers from Inserm formulated a hypothesis whereby this harmful effect might be related to the inappropriate activation by these creams of mineralocorticoid receptors located in the epidermis. These receptors, which are present in the kidney, heart, eye, and certain neurons in particular, reacted with aldosterone, a hormone that regulates the blood pressure. Moreover, previous studies also showed them to be highly sensitive to corticosteroids.

Application of corticosteroids to cultured skin causes it to become thinner: in 6 days, the thickness of the epidermis was reduced by one-third. The researchers then induced a pharmacological blockade of the receptors by adding specific antagonists to the corticosteroid treatment. The inability of the corticosteroid to bind to the mineralocorticoid receptors restores proliferation of the epidermal cells, and partially corrects epidermal atrophy.

From the clinical point of view, it turns out that spironolactone, a drug used for a very long time as an antihypertensive drug (and which has marketing authorisation), is an antagonist of the mineralocorticoid receptor. The researchers therefore tested a treatment based on spironolactone for 28 days in 23 healthy volunteers. Creams of different composition were applied to 4 areas of their arms:

– a cream containing a corticosteroid used in dermatology

– a cream containing spironolactone

– a combination of both drugs

– a placebo

The results obtained show that adding spironolactone to the corticosteroid significantly limits skin atrophy.

For Nicolette Farman, “This is a highly original piece of work, at the crossroads between endocrinology and dermatology, and brings together researchers in basic science and clinicians. Now it remains to reformulate this old drug for a new application, and test this product in patients with various skin diseases in order to confirm the reduction in side effects from corticosteroids without loss of efficacy.”

Female hands using skin cream

© fotolia

Preliminary results of the JIKI clinical trial to test the efficacy of favipiravir in reducing mortality in individuals infected by Ebola virus in Guinea.

Preliminary data from the JIKI clinical trial, which is testing the efficacy of favipiravir[1] in reducing mortality associated with Ebola, provide two important pieces of information:

• absence of efficacy in individuals who arrive at treatment centres with a very high level of viral replication and who already have serious visceral involvement,

• and encouraging signs of efficacy in individuals arriving at treatment centres with a high or moderate level of viral replication, who have not yet developed overly severe visceral lesions.

With this classification into two groups, we have a much better understanding of Ebola virus disease, and can redefine the role of antiviral monotherapies in the therapeutic arsenal used against the disease.

The trial, sponsored by Inserm and funded by the European Commission from the Horizon 2020 Initiative under the project title REACTION, is supported by two NGOs, Médecins Sans Frontières/Doctors Without Borders (MSF) and Alliance for International Medical Action (ALIMA); two laboratory networks, Belgian First Aid and Support Team (B-FAST) and European Mobile Laboratory (EMLab); the French Red Cross, and the French Military Health Service.

These preliminary data are being presented on Wednesday 25 February as a late-breaking abstract at the CROI international conference (Conference on Retroviruses and Opportunistic Infections) in Seattle.

Essai clinique JIKI Inserm – Ebola treatment centre in Guékédou Guinea © X Anglaret & D Sissoko /Inserm

Given the high mortality associated with Ebola virus despite high-quality symptomatic treatment, study of specific innovative therapeutic agents is essential. Potentially useful drugs against the virus include favipiravir (T-705), an antiviral drug already tested against influenza virus in adult humans (and well tolerated). The latter (no more than other potential treatments) has never been tested in humans for treating Ebola, but its efficacy has been demonstrated in vitro and in mice.

As part of the mission given to Aviesan to organise the research as a matter of urgency, the JIKI clinical trial, a phase II multicentre noncomparative trial, began in Guinea on 17 December 2014, to test the ability of favipiravir to reduce mortality in individuals infected by Ebola virus.

Sponsored by Inserm, and jointly funded by the European Commission, the JIKI trial is being conducted in partnership with MSF, ALIMA, the French Red Cross, EMLab, B-Fast and the French Military Health Service, and is taking place in four Ebola treatment centres in Guékédou (MSF), Nzérékoré (ALIMA), Macenta (French Red Cross) and Conakry (carers’ treatment centre).

In these centres, adults and children over one year of age with a positive Ebola PCR test who agree to take part (parental consent in the case of minors) receive treatment with favipiravir for 10 days along with basic care. Favipiravir is provided by FUJIFILM Corporation/Toyama Chemical Co., Ltd. Favipiravir comes in the form of 200 mg tablets (the tablets can be dissolved in a drink) and is administered according to the following dose regimen :

– Adults: Day 0: 2,400 mg at H0, 2,400 mg at H8 and 1,200 mg at H16, then 1,200 mg twice a day for 9 days;

– Children: doses adjusted to body weight.

The JIKI trial is being followed by an independent monitoring committee, which met on 11 December 2014, and on 5 January, 14 January and 26 January 2015. At this last meeting, the committee authorised the investigators to publish the interim data, which they judged to contain messages that should be quickly shared with the international community. These messages, obtained from the first 80 participants (69 adolescents or adults, and 11 children) are as follows:

– 42% of participants arrived at the treatment centres with a strongly positive PCR test (cycle threshold value, CT, < 20), reflecting a very high viral load . Of these patients, 81% had refractory renal failure and 93% died. In the three months preceding the trial, mortality among individuals presenting with the same features was 85%. Comparison of the trial and pretrial data shows that it is highly unlikely that favipiravir monotherapy will ultimately be proven to reduce mortality in this population with advanced disease.

– 58% of participants arrived in the treatment centres with a cycle threshold (CT) ≥ 20, reflecting a high or moderate viral load. Of these patients, 42% had renal failure, but only 15% died. In the three months preceding the trial, mortality among individuals presenting with a CT ≥ 20 was 30%. Comparison of the trial and pretrial data therefore leads us to hope that favipiravir monotherapy may reduce mortality in this population with less advanced disease.

For the researchers, these preliminary data encourage us:

– to continue the trial while trying to provide favipiravir treatment as soon as possible after the symptoms appear, so as to treat patients in whom viral multiplication can be controlled, and who have not yet developed visceral lesions (especially renal lesions);

– to explore other therapeutic options for patients who come to the treatment centres when their disease is too far advanced.

Yves Levy, the chairman and CEO of Inserm said: “The results of this non-comparative trial have to be confirmed using a larger number of patients. However, they open up other therapeutic opportunities in drug combinations, in particular for the treatment of patients suffering from more advanced stages of this disease. They also clearly show that research plays an essential role in tackling such epidemics. I would also like to stress that without the excellent Guinean-French cooperation, the pioneering role of the Médecins Sans Frontières (MSF) in this research, the fruitful partnerships with all NGOs involved, and the European Commission’s responsiveness, this progress could not have been accomplished.”

European Commissioner for Research, Science and Innovation Carlos Moedas said: “I am excited about the encouraging results of one of our EU-funded projects to tackle Ebola. We have preliminary evidence that the antiviral drug ‘favipiravir’ may be effective against early Ebola disease. If these results are confirmed by the ongoing clinical trial, it will be the first-ever treatment to be deployed against this deadly disease during the current outbreak. These results show the success of the European Commission’s quick reaction to the Ebola outbreak to support urgent research on several potential treatments and vaccines against Ebola with funding from our Horizon 2020 research programme. This is an astounding example of what the best brains can achieve with EU support when there is so much at stake. It shows how EU funding can lead to discoveries that save people’s lives and which are the result of rapid EU, international and industry cooperation.”

According to Agustin Augier, Secretary-General of Alima, “Those positive results will reinforce the confidence between affected populations and the treatment center. This therapeutic solution, even if partial, will significatively attract ebola patients to the treatment center. It is a significative step towards tackling the outbreak in the villages where it still goes on.”

“MSF is pleased to see that favipiravir seems to have a positive effect for certain patients suffering from EVD. But it also seems that the most vulnerable patients, the people that are most likely to die from the disease, don’t benefit at all from favipiravir. That fact, and the fact that these are only preliminary results, show that it is really too soon to start using favipiravir outside a trial environment. Research into favipiravir, and into other potential treatments for EVD, must be continued, and MSF is willing to play a role in these clinical trials,” says Dr. Bertrand Draguez, medical director of MSF.

[1] “Favipiravir is provided by FUJIFILM Corporation/Toyama Chemical Co., Ltd.”

This project has received funding from the European Union’s Horizon 2020 research and innovation programme

 

Immune cells commit suicide to prevent allergy

Scientists from the CNRS, INSERM and Université de Limoges, working in the Laboratoire Contrôle de la Réponse Immune B et Lymphoproliférations (CNRS/Université de Limoges)[1] have demonstrated that the production of type E immunoglobulins (IgE)[2]by B lymphocytes induces a loss in their mobility and the initiation of cell death mechanisms. These antibodies, present in small quantities, are the most powerful “weapons” in the immune system and can trigger extremely violent immune reactions or immediate allergies (asthma, urticaria, allergic shock) as soon as their levels rise, even slightly. These findings, published online in Cell reports on 12 February 2015, thus elucidate how our bodies restrict the production of IgE in order to prevent an allergic reaction.

image1

B lymphocytes under a confocal microscope (x1000). The cytoskeleton (actin molecules is labeled with a green fluorescent probe (phalloidin FITC). B lymphocytes with an IgM on their surface display protuberances (pseudopods) which testify to their mobility, while IgE+ B lymphocytes lose theses structures and become immobile.
© CNRS Laboratoire Contrôle de la réponse immune B et lymphoproliférations 

Immunity is based on cells, B lymphocytes, which carry or secrete antibacterial or antiviral “weapons”, the immunoglobulins (IgG, IgM, IgA, IgE) or antibodies. Although these weapons of immunity offer protection, they can also sometimes turn on us. This is the case for the most effective of antibodies, IgE, where even infinitesimal traces (these IgE are 100,000 times less abundant than other antibodies) can trigger extremely violent allergic reactions.

The lymphocytes that produce IgM, IgG or IgA are numerous, easily identifiable and persistent (as “memory cells”). For hitherto unexplained reasons, the cells that produce IgE are rare and have thus been the subject of very little study. In order to understand the mechanisms controlling IgE, the scientists first of all used genetic engineering to force cells to produce these antibodies in large numbers. They then succeeded in demonstrating two principal control mechanisms. They showed that as soon as a B lymphocyte carries an IgE on its membrane, it “freezes”, swells, loses its pseudopods[3] and becomes incapable of moving, although lymphocytes are generally highly mobile. The scientists also revealed that the lymphocyte activates several mechanisms leading to apoptosis, or programed cell death. This self-destruction causes the rapid elimination of lymphocytes carrying IgE, while other cells in the immune system are able to survive for up to several years.

During evolution, our bodies have thus developed several self-restriction mechanisms around one of their most powerful immune “weapons”, IgE. Because a cell carrying IgE can no longer move, it can only survive for a brief period — just long enough to play a short-lived protective role against parasites, toxins and poisons. It then self-destructs by committing a sort of “hara-kiri” which strongly reduces IgE production and hence the triggering of allergies. The scientists now wish to explore in more detail the different molecular pathways governing this self-restriction. Indeed, these may constitute numerous new therapeutic targets whose pharmacological activation could block allergies, or even permit the reduction of other pathological B lymphocytes, such as those involved in lymphomas.

image2

Internalization of membrane IgE (spontaneous endocytosis) contributing to weak IgE expression and the death of these cells. Visualization under a confocal microscope (x1000) of IgE+ B lymphocytes at 37 °C with anti-IgE antibodies. This labeling is able to demonstrate the internalization of membrane IgE indicated in blue (right). 
© CNRS Contrôle de la réponse immune B et lymphoproliférations

[1] In collaboration with an immunologist from the Laboratoire Microenvironnement et Cancer (INSERM/Université de Rennes 1).
[2] Immunoglobulins, or antibodies, are proteins secreted by type B lymphocytes in reaction to introduction into an organism of a foreign substance (antigen).
[3]  Deformations of the membrane that allow a cell to eat and “crawl”.

Elucidating the origin of MDR tuberculosis strains

A study has focused on the evolutionary history of the mycobacterium that causes tuberculosis, and more specifically on the Beijing lineage associated with the spread of multidrug resistant forms of the disease in Eurasia. While confirming the East-Asian origin of this lineage, the results also indicate that this bacterial population has experienced notable variations coinciding with key events in human  history. They also demonstrate that two multidrug resistant (MDR) clones of this lineage started to spread concomitantly with the collapse of the public health system in the former Soviet Union, thus highlighting the need to sustain efforts to control tuberculosis. Finally, this work has made it possible to identify new potential targets for the treatment and diagnosis of this disease. This study was carried out by scientists at the Centre d’Infection et d’Immunité de Lille (CNRS/Institut Pasteur de Lille/Inserm/Université de Lille) and the Institut de Systématique, Evolution, Biodiversité (CNRS/Muséum national d’Histoire naturelle/UPMC/EPHE), working in collaboration with a large international consortium[1]. Its findings were published on 19 January in Nature Genetics.
PhotoCP web

Tuberculosis bacilli visualized through scanning electron microscopy © Jean-Pierre Tissier (INRA, Villeneuve d’Ascq) et Franco Menozzi (Institut Pasteur de Lille)


Tuberculosis remains a major public health problem. The disease is  responsible for nearly one million-anda-half deaths each year, and strains of the infective agent that are increasingly resistant to antibiotics continue to emerge. The lineage of so-called Beijing strains is closely associated in particular with the spread of multi- and ultra-resistant tuberculosis in Eurasia. By studying the genetic fingerprints[2] of almost 5,000 isolates from this lineage, originating from 99 countries (i.e. the largest collection analyzed to date[3]), and then analyzing around a hundred bacterial genomes in more detail, the authors of this study were able to identify its original source and track the main stages in its spread.

The results of these genetic analyses indicate that the Beijing lineage emerged nearly 7,000 years ago in a region lying between northeastern China, Korea and Japan, whence it radiated throughout the world in successive waves associated with historical movements of human populations from east to west. In the modern era, the bacterial population first saw its size increase during the industrial revolution and the First World War. These phases of growth were probably linked to increases in human population density and deprivation respectively associated with these events. The only phase of  decline observed thereafter was concomitant with the widespread use of antibiotics during the 1960s. This decline ended in the late 1980s, and was  related to the HIV/AIDS epidemic and the onset of multidrug resistance.

This study has also shown that the more recent epidemic spread of the two  strains most closely associated with MDR in Central Asia and Eastern Europe coincided with the collapse of the public health system in the former Soviet Union. These findings underline the importance of maintaining highly  efficient disease control systems and developing new and more effective methods for  diagnosis and treatment.

In this context, the scientists identified a series of mutations and genes that might be connected with epidemic episodes and multidrug resistance. These genes constitute potential targets for treatment and for the development of new and more rapid diagnostic methods for multidrug resistance, based on  genomic sequencing.

[1] Consortium also led by the Borstel Research Center (Germany).
[2] Based on an internationally standardized molecular method, these analyses were performed by the team at the Centre d’Infection et d’Immunité de Lille, working in collaboration with the company Genoscreen.
[3] This collection was built up thanks to an international consortium, which includes the US Center for Disease Control.

Inserm is launching a development programme for a new generation vaccine strategy against the Ebola virus

A clinical trial project, coordinated by Inserm, involving the testing of a preventive vaccine against Ebola has been selected by the European Commission. The protocol plans to include participants throughout Europe and Africa to evaluate immune response and tolerance to a vaccine strategy named “prime boost”, based on the use of two candidate vaccines developed by Janssen, a pharmaceutical company of Johnson & Johnson.

Microscopic view of the ebola virus

© Fotolia


The development and rapid access to treatment and candidate vaccines are among the WHO’s recommendations to stop the transmission of the Ebola virus and prevent the international spread of infection. Since the beginning of the epidemic, the French and international scientific community has been actively working towards these objectives.

Inserm has established an academic partnership with the London School of Hygiene and Tropical Medicine (LSHTM), as well as an industrial partnership (Crucell Holland BV; one of Janssen’s companies), The University of Oxford and the Centre Muraz to develop a vaccination from Phase 1 to Phase 3 that combines two vaccines derived from viral vectors (Ad26.ZEBOV et MVA-BN-Filo[1]). This project has been selected for funding by the European Commission under the second call for IMI2 (Innovative Medicines Initiative) projects. As part of this programme, Inserm will conduct Phase 2 trials in Europe and Africa, coordinated by Prof. Rodolphe Thiébaut.

These Phase 2 trials will evaluate the tolerance and quality of the immune response to the vaccine strategy. These tests will supplement data from Phase 1 trials that are currently in progress in the United States, England and are soon to be conducted in Africa. The data will be available in March 2015 and will be critical to evaluating effectiveness in areas at risk.

“This strategy, unlike conventional immunization protocols that involve one or more administrations of the same vaccine, is based on the concept of a vaccination involving several steps with two different vectors that will expose the organism to the same antigens in several ways. This is a new approach in the development of a vaccine against Ebola” stated Prof. Yves Levy, Inserm CEO.

The Grant Agreement is currently being finalised. Definitive information on the project, including the budget, will be published once the agreement has been signed.

[1] Both viral vectors used are conventional vectors that are already widely used in humans in several vaccines for other infectious diseases.

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