Clever bacteria put human ingenuity to the test

How do bacteria manage to infect our body? What tactics do they use to slip through the cracks in our immune system? This is what the team of Thomas Henry, Inserm researcher, and his coworkers from the CNRS of Claude Bernard Lyon 1 University and the École Normale Supérieure de Lyon grouped within the International Center for Infectiology Research (CIRI) are trying to elucidate.  In a paper published in Nature Communication, the researchers studied a key component in the escape mechanism of bacteria and found, in humans, the major player involved in its detection.

Detecting the presence of the enemy is the first essential step in implementing a combat response. For our bodies, that role is played by the immune system,  which is confronted with various types of pathogens – particularly bacteria that employ every possible strategy to thwart its surveillance.

Normally, when invading the body, the bacteria betray their presence. The culprit, which is known as LPS and located in the bacterial cell wall, enables the human cells to recognize them and trigger an immune response. However, certain bacteria that are equipped with a more discreet form of LPS have a greater ability to pass under the immune system’s radar and increase their chances of infecting the body.

To understand the body’s defense mechanisms against bacteria, the researchers studied Francisella novicida, a pathogen model equipped with this discreet LPS.  This bacterium has the capacity to escape from within the innate immune cells (macrophages) which are supposed to destroy them.

Organizing the bacterial escape

Normally, the arrival of LPS within the cytoplasm of the macrophage is detected and the inflammatory response triggered, with the death of the cell halting the propagation of the pathogen. In reality, there is a constant race between bacterial multiplication and the detection systems of the host cell. Among the macrophage’s many alarm systems, Aim2 has been identified as being that which – in the mouse – is able to detect the arrival of these bacteria within the cytoplasm. However, it is impossible to reproduce the same result in humans. So, the challenge was then to understand how this counterattack takes place in humans.

Organizing the counterattack: at the right time, together!

This discovery also helps to explain why humans are more susceptible than mice to septic shock, which occurs when bacteria invade the blood or certain organs. Given that caspase-4 is particularly sensitive, the large quantities of LPS circulating in the blood provoke an immune system surge with irreversible life-threatening consequences. Despite everything, the diversity of the detection mechanisms and their partial redundancy help ensure that, following encounters with bacteria, humans often emerge the winner.

Identification of the functioning of caspase 4 and its cofactors represents a step towards the implementation of anti-inflammatory treatments in septic shock.

Illustration: Human macrophage (nucleus shown in blue) infected with Francisella novicida (red). The pathogen has escaped from the phagolysosomal compartment (shown in white) (one of the first defense mechanisms of the macrophage) but another defense protein, GBP2 (green), detects certain bacteria and enables caspase-4 to reveal the LPS of Francisella and implement antibacterial responses. Credit: Thomas Henry/Inserm

UK-France Summit. United Kingdom of Great Britain and Northern Ireland. Genomic Medicine, the Focus of the Agreement Supported by Aviesan

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To become the most advanced and competitive genomics research and healthcare system in the world: such was the ambition declared by Inserm, and its partners Aviesan and Genomics England Ltd, during the UK-France Summit on January 18, 2018. An agreement was signed by Sir John Chisholm, Executive Chairman of Genomics England Ltd, and Yves Levy, Chairman and Chief Executive Officer of Inserm, and Chairman of Aviesan, which heads up the governmental “French Plan for Genomic Medicine 2025”. They signed it in the presence of the President of the French Republic, Emmanuel Macron, and UK Prime Minister, Theresa May.

France and the United Kingdom share the same ambition to build and operate the most advanced and competitive genomics research and healthcare system in the world. This agreement is based on a partnership between two national programs: “100,000 genomes” by Genomics England and the “French Plan for Genomic Medicine 2025” supported by Aviesan.

From the discovery of the DNA double helix in 1953, which earned a Nobel Prize for Englishman Francis Crick, to the development of the use of genomics in medicine, the two nations have been undisputed international leaders in genomic medicine. This is embodied by the creation of two programs (“UK Genome” and the “French Plan for Genomic Medicine 2025” supported by Aviesan), from research to health care. Both countries have currently made the most ambitious, and most significant public commitments worldwide, to building infrastructure, mobilizing the necessary talents, and thus promoting globally renowned proposals in genomic medicine for the 21st century.

In practice, as part of their national programs, France and the United Kingdom are developing joint approaches to guarantee the harmonization and availability of the most relevant technological advances, most suited to changes in this sector.

By combining the strengths, efforts, and research and healthcare infrastructure of each nation, this agreement will thus make it possible to accelerate developments and achieve the defined objectives.

“This common, shared vision of genomics and our national strengths represents a genuine opportunity to intensify our partnerships and delve into the era of genomic medicine. Tailored therapies can only become a reality for patients through exhaustive knowledge of the human genome and by enlisting our best scientific talents,” asserts Yves Lévy, Chairman and CEO of Inserm and Chairman of Aviesan.

New Antiviral Targets Identified to Combat Dengue

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The dengue virus – like all other viruses – hijacks many of the host cell’s functions to accomplish its infectious cycle. For the very first time, researchers from Inserm, CNRS and Université Paris Diderot have recently identified all of the cellular factors that interact with the virus as it replicates. By providing proof of concept that some of these molecules can be inhibited, these scientists are paving the way for new antiviral therapies for dengue and also for other viruses in the same family, such as the Zika and West Nile viruses.

This research has been published in Cell Reports.

The dengue virus is a major public health problem that affects millions of people throughout the world, and for which no antiviral treatment is available. The only vaccine currently available is recommended by WHO only in highly endemic (national or regional) geographical contexts, and for people who have already been infected at least once. The virus causes the body to develop disorders, often harmless, ranging from mild to moderate fever, but may also cause hemorrhagic fever which can be fatal, especially in children.

The dengue virus genome is an RNA molecule that codes for three structural proteins forming the viral particle, and for seven non-structural (NS) proteins. The NS proteins are responsible for viral replication in the host organism and also control the host’s antiviral immune response. These two functions are essential to the survival of the virus in the infected organism.

During the infectious cycle, NS proteins assemble and recruit cellular factors, which are still relatively unknown, to form a replication complex essential to amplifying the viral genome. Understanding this crucial step in the life of the virus is paramount if researchers seek to discover strategies to curb infection.

By using miniature modified dengue virus genomes, the team led by Ali Amara from the “Pathology and Molecular Virology” laboratory (Inserm, CNRS, Université Paris Diderot), in collaboration with Dr. Pierre-Olivier Vidalain from the Pharmacological and Toxicological Chemistry and Biochemistry Laboratory (Université Paris Descartes, CNRS), has succeeded in purifying and analyzing the protein composition of the dengue virus replication complex. Researchers were thus able to identify a whole network of cellular factors which interact with NS proteins during the infectious cycle. Some act as virus restriction factors while others are essential to viral replication.

The researchers have also provided proof of concept that these interactions between the virus and host cell are potential targets for new antiviral therapies. To do so, they first demonstrated that the OST cellular complex, normally responsible for the transfer of sugar motifs on cellular proteins, is also hijacked by the virus for some of its own proteins. The scientists then explained that an inhibitor of OST complex activity, NGI-1, prevents glycosylation of certain viral proteins and strongly inhibits dengue virus replication, along with the secretion of virotoxin NS1, an early marker for severe forms of the disease. They have also shown that these results can be extrapolated to other pathogenic flaviviruses, such as the Zika and West Nile viruses.

Could the Biological Clock Be a Key Ally in the Fight Against Inflammatory Disease?

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What if the symptoms and seriousness of certain inflammatory diseases were linked to time of day? Researchers from Inserm, Institut Pasteur de Lille and Université de Lille[1] have been working on this hypothesis, after noting that the seriousness and mortality associated with fulminant hepatitis were dependent on the time at which the disease was induced. Their study, conducted on human cells and mice, shows that the anti-inflammatory action of a biological clock protein could prevent the onset of fulminant hepatitis, by alleviating symptoms and increasing survival rates.

This research has been published in Gastroenterology.


Fulminant hepatitis is a serious disease which leads to rapid deterioration of tissue and liver function in the patient, associated with blood coagulation disorders and irreparable brain damage. Although fulminant hepatitis can be caused by different factors, overdose with medications containing acetaminophen continues to be the main cause of the disease. Accumulation of acetaminophen in the body can cause cellular stress, which gives rise to an abnormal immune system response. This is expressed by excessive inflammation, which destroys hepatocytes and the liver. Until now, no specific treatment for fulminant hepatitis has been identified, and the only solution is liver transplant within 24 hours following onset of symptoms. Researchers from Inserm, Institut Pasteur de Lille and Université de Lille are focusing on the mechanisms underlying inflammation specifically in fulminant hepatitis, with a view to identifying potential avenues of treatment.


Starting from the observation that immune functions vary during the day, the researchers examined a biological clock protein called Rev-erbα and its potential role in regulating inflammation in fulminant hepatitis. This protein notably targets adipose tissue, together with liver, skeletal muscle and brain cells. It plays a major role in developing and regulating their circadian rhythm, i.e. the repetition of their biological cycle every 24 hours.


This new research, conducted on human immune system cells and on mice, showed that the inflammation also follows a circadian rhythm.

The researchers also observed that injecting a molecule potentiating the action of Rev-erbα reduced the inflammatory response which causes hepatocyte death in fulminant hepatitis. Mice having received the Rev-erbα-activating treatment demonstrated less severe forms of the disease, together with a higher survival rate.

As the same results were observed in vitro on human cells, these data indicate new avenues to be explored with a view to potentially developing a treatment for acute fulminant hepatitis or able to slow the progression of symptoms in patients awaiting transplantation.


Fulminant hepatitis is not the only disease involving the circadian molecular mechanism inhibited by Rev-erbα. Other diseases such as peritonitis, diabetes or even atherosclerosis display a similar imbalance in the inflammatory response due to the abnormal accumulation of toxins in the body. Inserm researcher Hélène Duez affirms that: “the results of this study could open up new prospects in preventing these diseases. They also offer new avenues for researchers, notably in terms of potential improvements in quality of life and longevity among patients suffering from chronic inflammatory disease.”

[1] Joint Research Unit 1011 nuclear receptors, cardiovascular diseases and diabetes (Inserm, Institut Pasteur de Lille, Université de Lille)

Beware of Sustained Ibuprofen Use in Men

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A recent study conducted by Inserm researchers within Irset[1] has shown that sustained ibuprofen use in young male athletes induces a hormonal imbalance known as “compensated hypogonadism”, usually observed in elderly males. This situation arises due to the negative effects of ibuprofen on testosterone production, and on the production of two other testicular hormones. These results have been published in Proceedings of the National Academy of Sciences.

Ibuprofen, which can be purchased without a prescription, is one of the most widely used medications in the population. This anti-inflammatory analgesic is mainly used for headache, toothache, chronic pain, influenza, fever, and certain rheumatic disorders. Furthermore, numerous studies have shown that vast quantities of ibuprofen are used by athletes, often as self-medication or when pressured by their professional circle. Conducted by Inserm researchers that have already demonstrated the potential harmful effects of aspirin and acetaminophen on adult human testicles[2] and those of ibuprofen on testicular development during pregnancy[3], and supported by colleagues from Rennes University Hospital, David Møberg Kristensen and his Danish colleagues, and researchers from LABERCA in Nantes, this new study brings together, in an unprecedented manner:

– A clinical trial involving 31 volunteer male athletes aged 18 to 35 years, half of whom take ibuprofen;

– Cultures of fragments of human testicles having been exposed to ibuprofen and taken from specimens related to therapeutic procedures or organ donation;

– And cultures of an immortalized human cell line.

The conclusions of the clinical trial show that levels of one pituitary hormone, luteinizing hormone (LH), rise strongly in men exposed to ibuprofen. This hormone plays a key role in controlling testosterone production. This increase has been shown to result from direct negative effects of ibuprofen on the expression of genes coding for several enzymes responsible for steroidogenesis, responsible for testosterone production.

Furthermore, ex vivo and in vitro studies have highlighted direct effects on testosterone production. Ibuprofen has been shown to inhibit a hormone produced by Sertoli cells – inhibin B – which is responsible for regulating follicle-stimulating hormone (FSH).

Moreover, the production of anti-Müllerian hormone by Sertoli cells is also inhibited, both in volunteers exposed to ibuprofen, and in the cultures of human testicle fragments.

Lastly, ibuprofen suppresses testicular prostaglandin production in ex vivo and in vitro tests.

Overall, this study shows that prolonged intake of high-dose ibuprofen (1,200 mg/day for 6 weeks) gives rise to severe endocrine disruptor effects in young males, leading to a condition known as “compensated hypogonadism”. This condition, usually observed in approximately 10% of elderly males, is generally associated with increased risks in terms of reproductive health, as well as general health.

According to Bernard Jégou, Inserm research director and research director at the EHESP French School of Public Health, who is the coordinator of this study, and joint lead author Christèle Desdoits-Lethimonier, research engineer at Université de Rennes 1, the conclusions of this research should require serious consideration: “there are male subpopulations who continuously take ibuprofen, namely men not suffering from chronic disease, such as high-level athletes. If compensated hypogonadism develops, they run the risk of increasing the hazards already associated with this medicinal product, impairing their physical condition (muscles and bones), and potentially jeopardizing their reproductive and even mental health”.

[1]  Irset: Research Institute for Environmental and Occupational Health

[2] Albert O, Desdoits-Lethimonier C, Lesne L, Legrand A, Guille F, Bensalah K, Dejucq-Rainsford N, Jegou B (2013) Paracetamol, aspirin and indomethacin display endocrine disrupting properties in the adult human testis in vitro. Hum Reprod 28(7):1890–1898.