Repurposing Drugs to Fight the Flu: a Phase 2 Clinical Trial for FLUNEXT


The VirPath team from the International Center for Infectiology Research (CIRI, Inserm Unit 1111 – CNRS Joint Research Unit 5308  – ENS Lyon – UCBL1), in collaboration with the laboratory of Dr. Guy Boivin (Canada Research Chair in Emerging Viruses, Infectious Diseases Research Center of the University Hospital of Quebec – Université Laval), has developed and validated an innovative strategy which involves the identification and direct exploitation of clinical samples from infected patients in order to select and use drugs marketed for the treatment of other viruses. A strategy known as “drug repurposing”. This program has been funded by Inserm, the French Directorate of Health Care Supply (DGOS), the French National Research Agency, the Auvergne Rhône-Alpes region, Université Claude Bernard and Université Laval.

This novel and accelerated bedside-to-bench and bench-to-bedside approach is particularly well-suited to acute respiratory infections because it enables the identification and rapid validation of new generations of antivirals which are more effective and treat a broader spectrum of diseases. In addition, the regulatory and financial benefits of this drug repurposing strategy are evident when compared with the long and very costly traditional new-drug development process. The team’s Drug Discovery platform has already demonstrated its potential (three international patents protecting eight repurposed drugs) with the identification of diltiazem (Tildiem®) – usually used in heart pathologies – as an anti-infectious agent in flu viruses.

On the basis of these findings, a phase 2 clinical trial, called FLUNEXT, led by Manuel Rosa-Calatrava, Inserm researcher and Julien Poissy (Inserm Unit 995, Lille Inflammation Research International Center) of Lille University Hospital, began in January 2018. The objective of this national trial is to evaluate the effects of diltiazem in combination with an antiviral, oseltamivir (Tamiflu®), for the treatment of severe flu infections. It intends to enroll 300 patients in ten intensive care units, over two periods of flu epidemic, with final results expected in 2019.

The validation of this strategy and the results already obtained have led to the creation of a startup called Signia Therapeutics. The laboratory’s research program will now be extended to include other respiratory diseases, such as human respiratory syncytial virus and human metapneumovirus, responsible for severe respiratory infections in young children and the elderly.

For more information on the VirPath team and CIRI:

The VirPath website

The CIRI website

Malaria: new insights into the mechanisms of parasite entry into liver cells


3D model of a Plasmodium protein mediating parasite entry into liver cells. ©O. Silvie

Malaria remains a major cause of mortality in the world, especially in Africa. The disease is caused by Plasmodium parasites, which are transmitted by mosquitoes. In the first hours following infection, parasites injected by the mosquito migrate from the skin to the liver, where they initially multiply before infecting red blood cells.

Until now, the mechanisms of parasite entry into liver cells remained poorly understood. Using cell culture systems, the team of Olivier Silvie, researcher at Inserm (Centre d’Immunologie et des Maladies Infectieuses) showed that the main species causing malaria in humans, Plasmodium falciparum and Plasmodium vivax, use distinct pathways to infect liver cells.

By employing a genetic approach in a rodent malaria model, the researchers identified a key parasite protein that determines which entry route is used. This work, performed by teams of Inserm and Universities of Paris, Strasbourg and Oxford-Mahidol, reveals new aspects of the host-parasite interactions.

The results open new perspectives for the development of antimalarial strategies aimed at blocking the early stages of infection.

Zika virus infects the human retina

Two Inserm teams involving Unit 1058, “Pathogenesis and Control of Chronic Infections” (Inserm/University of Montpellier/French Blood Transfusion Service) and Unit 1051, “Montpellier Institute of Neurosciences,” have just shown that Zika virus can infect the pigment epithelium of the human retina, and may thus be able to cause retinal damage.

This study is published in Journal of Virology.

Infection by Zika virus may result in several types of symptoms, particularly neurological damage of the Guillain-Barre type in adults and microcephalies in newborn children and infants. However, several studies suggest that the eye might be a preferred target of the virus, and ocular damage has been recently described in infected people.

Two Inserm teams have just demonstrated for the first time that the pigment epithelium of the human retina is permissive to infection by Zika virus. Using a human retinal pigment epithelium model derived from induced pluripotent stem cells, these teams were able to show that the virus replicates very efficiently in this type of cell. Moreover, the infection disrupts the integrity of the epithelium, and can thus have serious consequences for infected individuals, in terms of both visual function and viral transmission.

This study therefore emphasises the paramount importance of better characterising the ocular damage observed in certain individuals who have been infected by Zika virus

Narcolepsy-cataplexy, a sleep disorder, may have an autoimmune origin


© Fotolia

Narcolepsy-cataplexy is a rare and serious sleep disorder characterised by excessive daytime drowsiness and sudden loss of muscle tone. It is due to the loss of a population of neurons, known as the orexinergic neurons, located in the lateral hypothalamus. These neurons secrete a neurotransmitter, orexin, which stimulates the appetite and waking state. The aetiology of the disorder remains poorly known, although the genetic and environmental factors associated with narcolepsy, together with serological data, all point to a probable autoimmune origin.

In order to study the potential autoimmune aetiology, Inserm researchers at Unit 1043, the “Toulouse Purpan Pathophysiology Center” (Inserm/University of Toulouse/CNRS), have developed a mouse model that mimics narcolepsy. They thus generated mice expressing an autoantigen, haemagglutinin, specifically in the orexinergic neurons (Orex-HA mice). The mice were injected with effector T cells specific for this autoantigen.

CD4 T cells infiltrated the hypothalamus and triggered local inflammation, but did not induce destruction of the orexinergic neurons, in contrast to cytotoxic CD8 T cells. This neuronal loss led to cataplexy and sleep disorders in these mice, mimicking human narcolepsy.

“These results suggest that immunotherapy might be used to treat narcolepsy-cataplexy, and they identify a potential cellular target for this therapeutic strategy,” concludes Rolan Liblau, who conducted this work.

Septicaemia: the kidney protected by white blood cells

Septicaemia is a general inflammatory reaction secondary to an infection. Bacteria discharge into the blood, leading to fever, an increased heart rate, a drop in blood pressure, an increased breathing rate, and a pronounced fatigue of the body. Septicaemia is associated with significant mortality as it effects all of the organs. In France, it is estimated that there are around 70,000 cases of septicaemia per year with nearly 30,000 deaths, at a total cost of 2.8 billion euros.

The kidney lesions caused by septicaemia have been studied by Doctors Benjamin Chousterman and Alexandre Boissonnas in work performed in the Centre for Infectious Diseases and Immunology in Paris (Inserm/UPMC/CNRS) headed by Christophe Combadière, director of research at Inserm – in partnership with Prof. Didier Payen (Intensive care unit, Lariboisière hospital).

In an article published in the Journal of the American Society of Nephrology, the research team showed that certain white blood cells activated during the immune response (the monocytes) have a protective effect on the kidney tissue of mouse models of septicaemia.Inserm monocytes combadiere

Monocyte infiltration in a mouse model of septicaemia ©Inserm/Christophe Combadière

The protective effect would be induced by the adhesion of the monocytes to the site of the infection, in this case the kidney tissue. It is the activation of the “CX3CR1” monocyte receptor by the alarm signals – the “cytokines” produced at the site of infection – which reinforces this adhesion. A detailed analysis of the CX3CR1 gene variant in patients with septicaemia showed that the presence of allele I249 improves monocyte adhesion. The researchers found that, in these patients, the number of cases presenting an acute kidney failure was lower.

Receptor CX3CR1 would provide a prime target for therapies aiming to prevent organ failure during septicaemia. The results also highlight the protective function of monocytes, which to date have seldom been studied.

Huntingtin, architect of breasts

In the mammary gland, the lactiferous ducts are indispensable as they are the conduits through which milk is conveyed to the nipple. Within the cells lining them, the luminal cells, organelles and proteins are asymmetrically distributed. This “polarity” of the cells is the key element in their proper functioning.

Among the many factors involved in the correct establishment of this polarity, the researchers in a team formerly located at Institut Curie (Inserm/CNRS, Paris), and now at the Grenoble Institute of Neuroscience (Inserm/Université Joseph Fourier) have been focusing on huntingtin, better known for its role in Huntington’s disease, a neurodegenerative disorder. Surprisingly, it is present not only in the brain but in all cells of the body, and may be involved in the architecture and development of the mammary gland.glandes-mammaires

Section of mammary gland stained for basal cells (green), and an organelle (Golgi apparatus, red). The organelle is localised on the nucleus (blue) of the luminal cells, and is evidence of their polarity. © Salah ELIAS.

In this work, carried out by Sandrine Humbert’s team and published in Plos Biology, huntingtin was deleted from the luminal cells of mice, and the effect on the development of the glands and lactation was then studied. The lactiferous glands of mice that had lost huntingtin took longer to form, and showed abnormal architecture with a malformed lumen. At the same time, lactation was also affected: the protein content of the milk was reduced, and above all, these mice were unable to nurse their pups, resulting in serious weight defects.

Huntingtin determines the polarity of these cells, by interacting with many other factors. Its absence disrupts this polarity, which is the cause of the functional and structural disruption observed in the mammary gland.

“During tumour formation, we observe a similar disorganisation in cell polarity. Characterisation of the role of huntingtin is therefore essential for a better understanding of the pathogenic development that gives rise to breast cancer,” concludes Sandrine Humbert, Inserm Research Director.

A vaccine against house dust mite allergy?

House dust mite allergy affects over half of asthma patients. The major allergen, Der p 2, is recognised by nearly 90% of allergic patients. Continuous exposure to this allergen leads to a type of asthma characterised by bronchial constriction and inflammation of the airways, which in the most severe cases can lead to considerable disability and sometimes serious attacks and death.

“Desensitisation” is the only current treatment for respiratory allergies. It involves exposing patients to the allergen, usually by the sublingual route, so that their immune system gradually generates protective cells and antibodies. Thanks to technological advances and genetic engineering, so-called hypoallergenic peptides, derived from allergens and used as a vaccine, represent a new direction for immunotherapy, especially for house dust mite asthma. This strategy has the three-fold advantage of being effective in a short time, offering prolonged protection, and reducing the allergic side-effects of desensitisation.

In this work, carried out by researchers from Inserm and the French National Institute for Agricultural Research (INRA), in collaboration with researchers from the University of Vienna, Austria, a fragment of Der p 2 was generated by genetic engineering, and its protective effect against house dust mite asthma was then tested in a mouse model of asthma.

To accomplish this, mice were vaccinated with this peptide on 2 occasions: before and during allergic sensitisation to house dust mites. The researchers then measured bronchial obstruction in these mice in response to metacholin (a drug that induces bronchoconstriction), and demonstrated that vaccination with this peptide resulted in normal bronchial reactivity in asthmatic mice.

Furthermore, vaccination with this peptide induces anti-inflammatory activity, by reducing the chemical messengers that attract eosinophils and neutrophils to the bronchi and lungs, while reducing the T-lymphocyte activation and immunoglobulin E secretion responsible for the allergic reaction.

For the researchers, the protective role of vaccination, using a hypoallergenic peptide, is a very attractive therapeutic option for stemming the progression of asthma, especially in children at risk. Additional studies in animals are necessary before the first therapeutic trials in humans can be planned.

The peptide used is the subject of a patent filed by Inserm Transfert.

Segmented filamentous bacteria, partners in intestinal immunity, finally cultured in vitro !

Segmented filamentous bacteria (SFB) are bacteria from the Clostridiaceae family that colonize the intestines of many species, likely including humans, without causing disease; they live in symbiosis with epithelial cells and are involved in the maturation of intestinal immunity.

PhotoCP web

©Inserm/Martin, Sandra

Despite the vital role of SFB in establishing gut immune homeostasis in vivo in mice, scientists, for the past 50 years, have been unable to reproduce this symbiosis in vitro to shed light on the cellular and molecular interactions involved. Now, scientists from the Institut Pasteur, the Collège de France, Inserm/Imagine-Necker and the Université Paris Descartes have successfully cultured and reproduced the complex life-cycle of these bacteria outside their host for the first time.

A closer look at the symbiosis between SFB and their host

A single-celled intracellular offspring form of these bacteria attach themselves directly to intestinal epithelial cells, creating a mutually beneficial interaction between the bacteria and the host.

This non-pathogenic yet intimate relationship, which is established immediately after weaning, provides the bacteria with nutrients and, in turn, stimulates the development and maturation of the intestinal immune system. The delicate balance between these bacteria and their host protects the host from pathogens by strengthening both the epithelial barrier and the immune system. Animals lacking segmented filamentous bacteria in their intestinal flora are more susceptible to infection, even in adulthood.

The reproduction of this complex system in vitro should finally enable scientists to decode the dialog between the host and the bacteria and also to shed light on the way in which antibiotics can disrupt immune development as antibiotics lead to SFB disappearance from the gut.

Resident and recruited macrophages orchestrate the liver’s defense against infection

Macrophages are key cells of the innate immune system. By capturing and ingesting microbes in a process known as phagocytosis, they play an important role in defending host tissues against infection. There are two types of macrophage: tissue-resident macrophages, and bone marrow monocytes that circulate in the bloodstream and are recruited in tissues during infection where they become macrophages. Tissue-resident macrophages differ from monocyte-derived macrophages in terms of their origins, development and role.

Scientists from the Institut Pasteur, Inserm and Paris Descartes – Sorbonne Paris Cité University (Biology of Infections Unit, Inserm U1117, directed by Marc Lecuit) have demonstrated that liver-resident macrophages are rapidly killed by the pathogenic bacterium Listeria monocytogenes. This early death triggers the recruitment of macrophages from the bloodstream to the liver. These macrophages start by bringing the bacterial infection under control; then, in an unexpected development, they actually replace the liver-resident macrophages that have been killed by the infection.

This previously unknown mechanism sheds light on the way in which an organ such as the liver is able to control a bacterial infection and return to homeostasis once the pathogen has been eliminated. In immunological terms, this research also reveals a new functional interconnection between resident and recruited macrophages.


Illustration: Hepatic macrophage (in green) ingesting by phagocytosis pathogenic bacterium Listeria monocytogenes (in red). © Institut Pasteur

The pill might reduce the risk of thyroid cancer in women

Until the 2000s, the only established risk factor for thyroid cancer was exposure to moderate or high doses of ionising radiation during childhood or early adulthood. In order to better understand all the other factors that may be involved in thyroid cancer risk, a case-control study was conducted in eastern France. The study included 805 cases of thyroid cancer diagnosed between 2002 and 2006, and 876 control individuals. The researchers focused on hormonal and reproductive factors in women (633 cases and 679 controls). According to the results obtained, the risk of developing thyroid cancer was associated with a high number of pregnancies, the use of a drug to suppress lactation, or early age of menarche. Conversely, breastfeeding or a late first pregnancy was associated with a lower risk. The most innovative result of this study relates to the use of the contraceptive pill, which was also associated with a 30-40% reduction in the risk of thyroid cancer in these young women. Interpretation of this result will require better knowledge of the complex relationships that exist between endogenous and exogenous oestrogens, as well as better knowledge of thyroid function.x-ray  illustration of the female thyroid gland