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.

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

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.

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.

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.

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.

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