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Thanks to antiretroviral therapies, it is possible to grow old with HIV under control. However, this chronic infection may not leave cognitive function unscathed. That is why Alain Makinson (Translational Research on HIV and Infectious Diseases unit, Montpellier University Hospital, Université de Montpellier, Inserm, IRD) and his team were interested in exploring the development of neurocognitive impairment (NCI), such as diminished attention, memory and motor capacity, in patients living with HIV in the ANRS EP58 HAND 55-70 study. In their latest research, published in Clinical Infectious diseases, the scientists describe the results of their observations of 200 people living with HIV enrolled in six French centers. The data collected from these patients were then compared, using the same neurocognitive evaluation methods, with those of a control population of 1,000 people of the same age, sex and education taken from Constances – a cohort recruited from the general population, with over 200,000 volunteers. The researchers reveal that among those living with HIV between the ages of 55 and 70, the risk of developing mild (and in some cases, symptomless) neurocognitive impairment increases by 50%.

Thanks to antiretroviral therapies, people living with the human immunodeficiency virus (PLHIV) can bring it under control. However, while HIV is no longer their major cause of death – having decreased substantially since the advent of these therapies – other risks must be considered. Several recent studies have highlighted the increased prevalence of neurocognitive impairment (NCI) in PLHIV compared with uninfected individuals – an increase that is all the more pronounced in those whose virus is not controlled. However, this NCI could also be caused by cardiovascular factors or the onset of depression, which is more common in this population.

In order to try to determine the nature of the link between living with HIV and developing NCI (such as diminished attention, memory and motor capacity), Alain Makinson and his coworkers studied the data of 200 PLHIV, between 55 and 70 years of age, whose HIV was under control and who were enrolled between January 2016 and October 2017 in the ANRS EP58 HAND (HIV-Associated Neurocognitive Disorder) study. Each patient was compared with five HIV-uninfected individuals of the same age, sex and education, from Constances – a cohort recruited from the general population. The same methods were used for both populations when performing the cognitive tests and collecting the study data. All in all, 1,200 people took part in this study.

Although the impairments observed in the study were either mild or without apparent symptoms (i.e. with zero to low impact on daily activities despite abnormal test results), those living with HIV were more affected by NCI: 35% versus 24% for the control group.

The risk of developing NCI is therefore 50% higher for HIV-infected individuals compared with HIV-uninfected individuals, all other criteria being equal (age, sex and education).

Despite these highly robust results, a causal link between living with HIV and developing NCI cannot be established – for which there are several possible hypotheses. One is that HIV infection and its treatments cause recurrent brain inflammation. Another is that the complications associated with the immune deficiency can affect cognition before antiretroviral treatment is initiated, but without the subsequent deterioration occurring more rapidly in comparison with the general population. Finally, seropositivity could be associated with other risk factors (particularly drug use), which are difficult to measure fully in the two populations of this study.

The authors wish to continue to follow the same population over a longer period in order to better define the causes of NCI in this aging population and test the hypothesis of accelerated cognitive aging in PLHIV – particularly given that very few studies with a control group are available. Testing the brain inflammation hypothesis by collecting certain specific blood biomarkers represents another avenue for the team to explore in its quest to elucidate the mechanisms behind NCI.

Fibroblast infected with the chikungunya virus. © Inserm/Thérèse Couderc/Marie-Christine Prévost/Marc Lecuit

Chikungunya is an infectious disease caused by a mosquito-borne virus transmitted to humans. First detected in Africa, the virus has been responsible for recent epidemics in the Americas, Asia and the Indian Ocean – particularly the Reunion Island. Chikungunya is characterized by high fever and intense joint and muscle pain that can last for several months. The mechanisms of infection of human cells with the virus remain very poorly understood. Led by Ali Amara in collaboration with Marc Lecuit researchers from Inserm, Institut Pasteur, CNRS and Université de Paris have identified a protein that is crucial in order for the virus to replicate within its target cells. This research, published in the journal Nature, opens up therapeutic avenues in the fight against chikungunya.

Originally from Africa, chikungunya is aptly named. It derives from a word in the Kimakonde language, meaning “to become contorted”, because the severe muscle and joint pains endured by the patients prevent them from moving normally or performing their daily activities.

While the clinical manifestations of the disease are well understood, the mechanisms by which the virus infects human cells and multiplies remain poorly elucidated. Several studies had already identified certain host cell factors implicated in the replication of the virus. However, none had succeeded in explaining why the virus preferentially targets the muscle and joint cells, causing these clinical signs.

Researchers from Inserm, CNRS and Université de Paris led by Dr. Ali Amara at the AP-HP Saint-Louis Hospital Research Institute in Paris, in collaboration with Marc Lecuit’s team from Institut Pasteur, Inserm and Université de Paris, have identified that the FHL1 protein is a key cellular factor for the replication and pathogenesis of chikungunya. FHL1 is a molecule present mainly in the muscle cells and fibroblasts, the preferred targets of the virus. Usually, FHL1 contributes to healthy muscle physiology and it is now thought to be diverted from that function by the virus to ensure its replication in the target cells.

To conduct this study, Amara’s team used the CRISPR-Cas9 technology to systematically screen the genome of human cells in order to identify the host factors necessary for viral replication. In doing so, it isolated the gene coding for the FHL1 protein. The team then conducted a series of experiments showing the incapacity of the virus to infect cells whose FHL1 expression had been abolished.

In addition, the researchers have shown that the virus was incapable of multiplying within cells derived from patients suffering Emery-Dreifuss muscular dystrophy – a rare genetic disease. This muscle disease is the result of mutations of the FHL1 gene responsible for the breakdown of the FHL1 protein. The researchers have shown that the cells of these patients are resistant to the virus.

Finally, the researchers performed in vivo experiments in mice whose Fhl1 gene was invalidated. They have shown that these animals are totally resistant to infection and do not develop the disease, whereas the virus multiplies and causes major muscle lesions in mice expressing a functional FHL1 protein. These observations demonstrate that the FHL1 protein plays a key role in chikungunya virus replication and pathogenesis.

The precise role played by FHL1 in the viral infection is not fully understood. The researchers have discovered that FHL1 interacts with a viral protein known as nsP3. It is when binding to this that FHL1 participates in the replication of the virus.

“We now want to understand this interaction in molecular detail. The next step is to define why FHL1 is so specific to the chikungunya virus, and to decipher its mechanism of action at the molecular level. Elucidating the molecular structure of the FHL1-nsP3 complex could represent a major step forward in the development of antivirals that block the replication of the virus“, emphasize Ali Amara and Laurent Meertens, the Inserm researchers in charge of the study.

At present, only symptomatic treatments are available for patients infected with chikungunya.

Escherichia coli © Inserm/Cloup, Emilie/Nougayrede, Jean-Philippe

For more than a century, the Nissle 1917 strain of the bacterium Escherichia coli has been used as a probiotic to treat gastrointestinal disorders. However, this bacterium also produces a toxin, colibactin, which has deleterious effects on host DNA and might cause colon cancer. It is therefore crucial to understand the mechanisms at play in the strain if we wish to limit undesirable side effects. In a recent study, researchers at INRA, INSERM, the University of Toulouse III – Paul Sabatier, and ENVT managed to decipher certain pathways by which Escherichia coli Nissle 1917 produces both beneficial and toxic compounds. They then successfully created a modified strain with the same probiotic properties but an unactivated version of the toxin. This work was published on September 23, 2019, in PLOS Pathogens.

A German doctor discovered the bacterial strain that became known as Escherichia coli Nissle 1917 during World War 1. There had been an outbreak of dysentery in a group of soldiers; only one remained unafflicted. The doctor, Alfred Nissle, isolated the strain from this soldier and used it to treat other soldiers. Since then, E. coli Nissle 1917 has been used as a probiotic to treat various gastrointestinal disorders.

In 2006, researchers at INRA, INSERM, the University of Toulouse III – Paul Sabatier, and ENVT discovered that the genome of E. coli Nissle 1917 contained a group of genes that jointly encode a toxin: colibactin. In certain E. coli strains, colibactin acts as a virulence factor and can promote colon cancer. Until now, researchers had been unable to decouple the strain’s probiotic properties from its toxic side effects. It was therefore necessary to delve into the mechanisms underpinning both the strain’s synthesis of beneficial compounds, which make it a probiotic, and its synthesis of harmful compounds, notably colibactin, which can have negative impacts.

In a new study, this same team of researchers uncovered the important role played by the protein ClbP. It is an enzyme that has a key function in the strain’s probiotic action but that also activates colibactin. 

Using this discovery, the scientists were able to create a strain in which a tiny relevant portion of the enzyme was modified. This strain had the same probiotic properties as the original but could not activate colibactin, negating its toxicity. In vivo assays in mice confirmed the functionality of the new strain. Mice infected with Salmonella typhimurium (one of the bacteria that can cause dysentery) developed less severe symptoms of salmonellosis when treated with the modified E. coli Nissle 1917 strain.

This research underscores the importance of taking a closer look at the bacteria that we use as probiotics. Indeed, like traditional medications, they can have side effects.

Illustration of the experimental approach © INRA, INRA, Eric Oswald

WHO©C. Onuekwe

The World Health Organization (WHO) recommends a single dose of the yellow fever vaccine for individuals aged 9 months or older living in or traveling to areas at risk of disease transmission, but there is a lack of data on its long-term efficacy when administered to infants. José Enrique Mejía, Inserm researcher at Unit 1043 Center for Pathophysiology of Toulouse Purpan and Cristina Domingo from the Robert Koch Institute in Berlin have recently shown that around half of children initially protected by the vaccination at 9 months of age lose that protection within the next 2 to 5 years, due to disappearance of the neutralizing antibodies. This research has been published in The Lancet Infectious Diseases.

Yellow fever is a viral infection spread by various species of mosquito and is rife in 34 countries in Africa and 13 in Latin America. Infection may be asymptomatic and go unnoticed or, on the contrary, it may progress rapidly to severe illness with fever, headache, muscle pain, nausea, vomiting and fatigue. The virus attacks the liver cells, often causing jaundice from which the disease gets its name. Severe bleeding occurs in 25 to 50 % of cases, with high levels of mortality observed 7 to 10 days after the onset of symptoms.

Since 2013, WHO recommends a single dose of the vaccine for life-long protection. This recommendation is based on proof of long-term efficacy, in vitro and in vivo, established in adults and children over 2 years of age.

Their study verified whether children to whom the vaccine was administered at around 9 months of age were still protected several years later. The team studied two cohorts, one from Mali (587 children) and the other from Ghana (436 children), in whom the levels of specific antibodies to the yellow fever virus had been measured 4 weeks after vaccination. They then repeated the measurement several years later, with findings from previous studies enabling them to estimate that levels above 0.5 IU/ml should protect children from infection.

In the Malian cohort, 4.5 years after vaccination, only half of the children continued to present levels of antibodies above 0.5 IU/ml. And 19.3 % presented detectable antibodies but at levels below this recommended threshold (<0.5 IU/ml). The proportion of children seropositive for these antibodies was therefore 69.7 % as opposed to 96.7 % just after vaccination.

In the Ghanaian cohort, 2.5 years after vaccination, only around 30 % of children continued to be protected against infection and 11.7 % continued to present specific antibodies but in low concentrations (<0.5 IU/ml). All in all, 39.4 % of the children were considered seropositive as opposed to 72.7 % just after vaccination.

Irrespective of the differences in vaccine efficacy between these two groups, which could be explained by ethnic and environmental factors (urban/rural population, seasonality of vaccination, diet, exposure to other infectious agents, etc.), the results in both cases show a substantial fall – practically by half – in the levels of protective antibodies in the years following vaccination, and which predict the absence of protection against infection for large numbers of children.

“Our data suggest that a booster may be necessary when the 1^st vaccination is performed in 9-12-month-olds, but we will need more precise knowledge of the decrease in antibodies over time. Maintaining immunity to the virus during childhood and in adulthood is fundamental for obtaining vaccine coverage beyond the threshold of 80 % of the population in order to prevent the risk of epidemic”, concludes Mejía.

©Photo by Gesina Kunkel on Unsplash

Prebiotics are currently a preferred treatment for certain metabolic disorders, as they can restore the balance of dysfunctional gut microbiota, and improve the body’s metabolism. However, these substances have to be used at high doses, which can result in patients experiencing bloating and flatulence. A research group led by Matteo Serino, Inserm researcher at the Digestive Health Research Institute (Inserm/Inra/ENVT/UT3 Paul Sabatier), has recently shown three plant extracts to have prebiotic effects in obese/diabetic mice, with a shorter duration of treatment and at lower doses to the prebiotics currently in use. For Matteo Serino, this raises the question: do we need to reconsider the protocol for prebiotic administration? These results have been published in Molecular Nutrition & Food Research.

Dysbiosis of the gut microbiota corresponds to an imbalance in the populations of gut microorganisms and/or a change in their activity. This imbalance is often associated with metabolic disorders such as obesity and type 2 diabetes.

It has been shown that such dysbiosis can be targeted with prebiotics, long molecules that are not digested by the body but which increase the growth and activity of certain bacteria and thus improve patients’ carbohydrate and lipid metabolism. However, the duration of treatment is often greater than 4 weeks, and the effective dose at which an improvement in health starts to be observed can result in adverse effects such as bloating and flatulence.

A team of researchers from the Digestive Health Research Institute sought to identify other substances that might have a prebiotic effect. This led them to study extracts from three plants that had previously shown some beneficial effects: a red alga called Porphyra umbilicalis, the leaves of the lemon balm plant, Melissa officinalis L., and fruit extracts from an Indian plant, Emblica officinalis Gaertn.

The researchers administered these extracts to obese and diabetic mice for just two weeks, and at doses proportionally lower than the effective doses of traditional prebiotics.

The team considered a range of criteria in evaluating the individual prebiotic effects of the plant extracts.

The researchers first measured the impact of these substances on the diversity (the number of bacteria from different populations) and activity of the gut microbiota before and after treatment. “Our results were broadly positive for microbial diversity, with all the extracts increasing the abundance of at least one group of bacteria,” explains Matteo Serino, the Inserm researcher who led the study.

Beyond the impact on the microbiota, improved metabolism was one of the key criteria for evaluating the prebiotic efficacy of an extract. The research team observed that each of the three substances produced an increase in the gut of the quantity of the various short-chain fatty acids that are produced by bacterial metabolism of prebiotics and contribute to improving host metabolism.

The researchers also measured the presence of various markers in the blood that would enable them to demonstrate any metabolic improvements. The best result was obtained with the extract from the red alga P.umbilicalis. The researchers measured a 30% decrease in the level of blood triglycerides, large molecules with long-chain fatty acids that are present in excess levels in the blood of patients with metabolic disorders. This finding thus suggests an improvement in lipid metabolism among the treated animals.

“What’s interesting to note is that all of these effects were observed after just two weeks of treatment, and at low doses. This suggests the need for further studies to find out if this type of treatment could be effective in humans, and to test whether the extracts currently in use remain effective when given at low doses, thus limiting their side effects. That would mean reconsidering the existing protocol for prebiotic administration,” concludes Matteo Serino.

Artist’s representation of cells and placenta © Fabrice Hyber – Organoïde-Institut Pasteur/Fluorescence microscopy of fused cells (in green) and nucleus (in blue). © Institut Pasteur

Discovery of a cellular mechanism involved in abnormal placental development during some high-risk pregnancies.

High-risk pregnancies occur frequently and may be caused by various factors. It is estimated that 10 to 20% of pregnant women miscarry during their first trimester of pregnancy. Slow fetal growth may also arise as a result of maternal infection with certain microbes, parasites or viruses (such as toxoplasmosis or infection with rubella virus, cytomegalovirus, herpes or Zika) or because of genetic or autoimmune diseases. Teams from the Institut Pasteur, the CNRS, Inserm, Necker-Enfants Malades Hospital (AP-HP) and Université de Paris have identified a new cellular mechanism that alters placental development, potentially causing serious complications during pregnancy. The mechanism is linked with the production of interferon, a molecule produced in response to infection, especially viral infection. The findings are published in Science on July 11, 2019.

The placenta is both a surface for exchange and a barrier between mother and fetus – it delivers nutrients needed for fetal growth, produces hormones and protects the fetus from microbes and the maternal immune system. The external layer of the placenta, known as the syncytiotrophoblast, is composed of cells which fuse together, forming giant cells that are optimized for the placenta’s barrier and exchange functions. Cell fusion is mediated by a protein known as syncytin. If the syncytiotrophoblast fails to form correctly, it can cause placental insufficiency and hinder fetal development. An abnormal syncytiotrophoblast can be observed in conditions such as slow intrauterine growth, the lupus and in women whose fetus has Down syndrome.

Interferon is a substance produced by immune cells during infection to combat viruses and other intracellular microbes. High levels of interferon are observed in autoimmune or inflammatory diseases such as lupus, and also in some infections. In this study, the scientists demonstrated that interferon is responsible for placental abnormality and that it acts by preventing syncytiotrophoblast formation. Specifically, interferon induces the production of a family of cellular proteins known as IFITMs (interferon-induced transmembrane proteins), which block the fusion activity of syncytin.

IFITM proteins are beneficial since they prevent viral fusion with cellular membrane, thereby stopping viruses from entering and multiplying within cells. The scientists used experimental models and human cells to demonstrate that this beneficial effect can nevertheless be harmful if IFITM proteins are produced in an important level in the placenta.

“Identifying the role of IFITMs gives us a better understanding of the mechanisms involved in placental development and how it may be disrupted during infections and other diseases,” comments Olivier Schwartz, Head of the Virus and Immunity Unit at the Institut Pasteur and joint last author of the paper. The scientists want to investigate whether placental pathologies of unknown etiology, such as some early spontaneous abortions and occurrences of preeclampsia, also involve IFITM proteins. In the longer term, blocking the effects of IFITMs could represent a new therapeutic strategy to prevent interferon-related placental abnormality.

In addition to the institutions mentioned above, this research was funded by the ANRS, Sidaction, the French Vaccine Research Institute (VRI), LabEx IBEID and the European Research Council (ERC).