An infection from the cytomegalovirus (CMV), a virus belong to the herpesviridae family, usually goes unnoticed in a healthy subject, but in pregnant women, it can be harmful to the foetus. Nabila Jabrane-Ferrat, research officer of the CNRS Physiopathology Centre at Toulouse Purpan (Inserm unit / université Toulouse III – Paul Sabatier / CNRS), working with The “Immunity, Gestation, Therapy” research team led by Philippe Le Bouteiller, an Inserm research director, has demonstrated that certain immune cells from the mother located at the foeto-maternal interface are capable of fighting the infection in order to protect the foetus. This work was published in the review Plos Pathogens on April 4, 2013.

Pregnancy induces major modifications in the uterus that are necessary to provide the needs of the foetus. Following the implantation of a fertilized egg, the wall of the uterus (the endometrium) is massively infiltrated with a specific population of immune cells known as decidual Natural Killer cells (dNK), that come from the mother.

The functions of these immune cells are finely regulated during pregnancy. In the endometrium, their function is not to kill, but to protect to allow successful implantation of the embryo. dNK cells release soluble factors that help the embryo to implant into the maternal tissue. They contribute to exchanges between the mother and the fœtus and are in direct contact with the placenta. By providing an enriched microenvironment, dNK cells play a major part in pregnancy.

The authors of the study published this month wondered whether these cells that are “armed to kill” could have their gregarious instinct aroused in the event of an attack by a pathogenic agent. To this end, they studied the action of the dNK cells when the mother was infected by CMV during pregnancy.

Congenital infection by the CMV is a major public health problem that affects between 0.2 and 0.5 percent of newly-borns in France and is a known cause of foetal fatality. CMV contamination occurs by close contact with affected persons or healthy carriers. Therefore, pregnant women must respect the classic rules of hygiene to avoid infection during their pregnancy, since the risk of foetal contamination is between 30 to 50%.

There are no clinical signs of CMV in a healthy adult; but it is dangerous for the foetus if the mother becomes infected. The virus passes into the mother’s bloodstream, crosses the placental barrier and infects the cells in the foetus, causing serious damage, even death to the foetus. Congenital CMV infection induces placental development problems and remodelling of the uterine arteries that can be detected by ultrasound scanning.

Researchers have observed phenotype and functional changes in maternal dNK cells. In addition, analysis of tissues from terminations of pregnancy due to CMV has shown that dNK cells are capable of migrating to the actual site of the infection in the placenta.

Quite unexpectedly, the researchers found that dNK cells become cytotoxic in order to kill off infected cells and fight infection.

© N. Jabrane-Ferrat / Inserm. In red and greed above: the NK cells attempting to make their way to the infected cell (in glue and green).

These results suggest that dNK cells could protect the foetus from maternal CMV infection. They open the way for the development of new treatments. The next step is to figure out how to trigger a massive cytotoxic reaction by the dNK cells when faced with the virus.

How is it that certain patients infected by HIV have immune cells that are capable of controlling the infection? Victor Appay, INSERM Research Director (Mixed INSERM  Research Unit 945 “ Immunity and Infection” / Université Pierre and Marie Curie / Hôpital Pitié-Salpêtrière (AP-HP)) and his colleagues have succeeded in identifying the molecular characteristics of certain T lymphocytes that have the specific property of being able to detect and control HIV and its mutant versions. Their work was published in 22 March 2013 in the Immunity journal and has received support from the ANRS. 

Today, according to the OMS, 34 million people are infected with HIV, yet only 1.3 million sufferers in the poorest countries are being treated and 6,800 people a day are infected by HIV.

The Human Immunodificiency Virus (HIV) attacks the cells of the immune system and destroys them or renders them ineffectual. Acquired Immunodeficiency Syndrome (AIDS) is the final stage in HIV infection. It may appear after 10 to 15 years.

The inherent danger in a virus lies very much in its ability to develop multiple strategies to escape detection by the immune system. HIV is no exception to the rule. HIV is known to mutate and adapt in each individual and his/her major histocompatibility complex (MHC).

HIV is a good example of how a pathogenic agent can evolve and mutate by creating what is known as a new variant, in order to circumvent its host’s immune system.

In certain cases, however, the immune system is able to react to control these mutant pathogens.

The molecular basis of the process has not been clearly established hitherto, but this is what researchers have now been able to do. Their work makes it easier to under the mutual adaptation mechanism between the immune system and HIV.

In order to better understand how HIV works, Victor Appay, INSERM Research Director, in collaboration with his colleagues at Cardiff University (United Kingdom), Kumamoto University (Japan) and Monash University (Australia), and with the support of the ANRS, studied the cells of patients whose immune response proved effective against the virus and its variants. These patients, all of them from the ANRS Primary Infection cohort, were monitored from the time primary infection with HIV was diagnosed. The detailed study focused on the response caused by the T CD8+ lymphocytes of patients infected by HIV and in whom these cells were particularly well preserved and functional.

In other words, these cells not only managed to control and reduce the replication of HIV but even of its variants, something that is not the case in patients who develop the full-blown disease.

This protective immune response is possible due to certain T CD8+ lymphocytes, that are known as “cross reactive”. They have a receptor on the surface whose structure gives then the special ability to recognise not only the non-mutant virus but even its mutant variants. This discovery is the first to really pinpoint how HIV can be controlled by certain T CD8+ lymphocytes.

The study highlights the complexity of the forces and mechanisms that lead to the development of the virus and the way it alters the immune system during the course of HIV infection. A better understanding of immunological determinants as the basis for control of replication of HIV is essential for the development of effective vaccines. In fact, the choice between immunogens and adjuvants in the development of vaccines against HIV needs to be rationalised in order to encourage the production of T CD8+ lymphocytes that are particularly skilled at recognising the wilder and mutant forms of the virus.

The HOMAGE (Heart OMics in AGEing) project, coordinated by the French National Institute of Health and Medical Research (INSERM), has been awarded a grant by the European Commission for a 6 year period. The project aims to identify and validate specific biomarkers of heart failure in order to prevent the development of the disease affecting elderly population. 17 research groups from 10 countries will collaborate to investigate new ways of preventing heart failure. The project will use an innovative ‘omic-based’ approach which investigating simultaneously a huge amount of genes, proteins and metabolites.

The 17 partners will meet at Nancy on February 22nd for the kick off meeting of HOMAGE.

Professor Faiez Zannad, Head of the Centre d’Investigation Clinique Pierre Drouin Inserm U9501 and Inserm Unit 1116 based in Nancy, is the project coordinator.  The 12 million euros grant of the European Commission will be dedicated to the HOMAGE consortium for research on heart failure, a serious illness altering myocardial activity which affects more than 6.5 million persons in Europe. Indeed, the prevalence of heart failure is increasing worldwide due to an ageing population as well as a rising trend of risk factors for heart disease such as diabetes, obesity and hypertension.

Heart failure is a major cause of mortality and morbidity in the world and remains the most frequent cause of hospitalization for patients over 65 years old.

The costs related to heart failure have been estimated around 1.5 billion euros per year in France[1].

Photo : ©Serimedis/Inserm

Despite important progress in the treatment including new drugs, new medical devices and innovative disease management programmes, the diagnosis of heart failure is often difficult in older adults with co-morbidities. Screening tests are usually based on blood pressure, glycaemic and cholesterol control. Although they are useful to detect high risk patients, they are limited regarding their sensitivity and specificity. During the past decade, promising biomarkers such as natriuretic peptides have been identified to diagnose heart failure, but their predictive value remains relatively poor. The HOMAGE consortium is willing to validate more specific and more sensitive biomarkers which should facilitate an early detection of the disease in patients at risk.

To achieve this goal, the consortium agreed on the use of an ‘omic-based’ approach. This approach aims to validate promising biomarker candidates by crossing a large volume of data (genomics, proteomics, miRNomics, transcriptomics and metabolomics). This would permit scientists to understand new pathophysiological mechanisms, signaling pathways and identify new therapeutic targets to prevent heart failure.

The HOMAGE consortium will manage cohorts for a total of 30 000 patients. The European researchers will firstly identify biomarker candidates in blood and study their predictive value for heart failure and common co-morbidities associated with ageing (renal impairment, cognitive disorders…). Subsequently, HOMAGE will lead a clinical trial to look for novel treatments of heart failure that can be targeted specifically to those patients at risk.

This trial will allow identifying patients’ omics based biomarker profiles most likely to predict response to treatment with the better benefit/risk ratio, an attempt into personalized medicine.

Weak concentrations of bisphenol A are sufficient to produce a negative reaction on the human testicle. This has just been shown experimentally for the first time by René Habert and his colleagues (UMR Cellules souches et Radiations [UMR Stem Cells and Radiation], Inserm U 967 – CEA – Paris Diderot University) in an article that appeared in the journal entitled  Plos One.

In this new study, researchers observed that exposure of human fœtal testicles to bisphenol A reduces the production of testosterone, and of another testicular hormone that is necessary for the testicles to descend into the sacs in the course of fœtal development. A concentration equal to 2 micrograms per litre of bisphenol A in the culture medium was sufficient to produce these effects. This concentration is equal to the average concentration generally found in the blood, urine and amniotic fluid of the population.

Testosterone is known to be produced by the testicle during the life of the fœtus, imposing masculinisation of the internal and external genitals which, in the absence of testosterone, develops spontaneously in the female direction. Furthermore, it is likely that testosterone also plays a role in the development of the testicle itself. Consequently, the current exposure of pregnant women to bisphenol A may be one of the causes of congenital masculinisation defects (of the hypospadia and cryptorchidism types) the frequency of which has doubled overall in the past 40 years. According to René Habert, “it is also possible that bisphenol A contributes to a reduction in the production of sperm and  the increase in the incidence of testicular cancer in adults that have been observed in recent decades”.

Furthermore, researchers have compared the response to bisphenol A in human fœtal testicles to those in the fœtal testicles of rats and  mice. “We have observed that the human species is far more sensitive to bisphenol A than the rat and the mouse. These results should encourage greater caution in regulatory toxicology in the extrapolation of data obtained on animals to define tolerable exposure thresholds in human health”, explains René Habert.

Finally, the researchers show in this article that Bisphenol A acts through a mechanism that is non-standard and that remains unknown but that it is important to identify in order to better understand the action of endocrine disruptors.

©Fotolia

The researcher Capucine Picard, working with the team from Inserm unit 980 “Human genetics and infections diseases”/Université Paris Descartes under the leadership of Jean-Laurent Casanova, along  with researchers from a CNRS/Institut Pasteur laboratory headed by Alain Israël have succeeded in identifying the part played by the HOIL1 gene in cases of paradoxal association of an immune deficiency with a chronic autoinflammatory deficiency and a muscular deficiency in 3 children from 2 different families. This study once more highlights the importance of genetics in the body’s response to infectious agents. These works were published on line in the review Nature Immunology, of 28.10.12.

The science of genetics of infectious diseases arose from the observation that there is a wide variability of resistance to diseases from one person to another; that the same pathology could be fatal to one person, while benign or asymptomatic in others. The study also demonstrated that the predisposition to an infection is due to genetic particularities that result in variations in the molecular mechanisms of the immune response.

The 3 children, 2 of whom were monitored at the Hôpital Necker sick children’s hospital, suffered simultaneously from 3 pathologies: invasive bacterial infections (pneumococcus or other), an autoinflammatory disease (inherited recurring fevers) and amylopectinosis (a muscular deficiency that can affect the cardiac muscles in particular). The fact that 2 siblings suffered from the same symptoms drew the researchers’ attention to the hereditary genetic cause of this disease.

The team then carried out in-depth genetic studies in an attempt to identify the genetic defect responsible for these 3 observed pathologies: mutations of the HOIL1 gene.

Incomplete expression of this gene causes a dysfunction of the immune system. However, what makes this pathology unique is the fact that the genetic defect does not express in the same way, depending on the type of cells involved in the immune response. On the one had, this mutant gene is responsible for an over-reaction of leucocytes, which explains the autoinflammatory disease. On the other hand and quite to the contrary, this same genetic defect inhibits a response from other cells, which explains the susceptibility of these children to bacterial infections.

The HOIL1 molecule, derived from the gene of the same name, is responsible for an instability of the LUBAC complex that plays an important part in transmitting the signal received by the immune system cells in case of infection. This suggests that the genetic defect on HOIL1 in humans is responsible for a knock-on defect in the LUBAC complex, and that the LUBAC complex controls the immune response differently depending on the cell types involved.

Previously, the LUBAC complex had only been studied in mice. This is the first time that this deficiency has been detected in a human. For the moment, only 3 patients inFranceand inItalyhave been identified with this HOIL-1 deficiency. The discovery of this new genetic defect may allow us to identify new patients in other regions of the world.