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1. Molecular determinants of SR-B1-dependent Plasmodium sporozoite entry into hepatocytes

Author

Langlois, Anne-Claire, Manzoni, Giulia, Vincensini, Laetitia, Coppée, Romain, Marinach, Carine, Guérin, Maryse, Huby, Thierry, Carrière, Véronique, François-Loïc, Cosset, Dreux, Marlène, Rubinstein, Eric, Silvie, Olivier, Centre d'Immunologie et de Maladies Infectieuses (CIMI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Unité de recherche sur les maladies cardiovasculaires et métaboliques, UMR S 1166, Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Sorbonne Université (SU), Hôpital St Antoine, Virus enveloppés, vecteurs et immunothérapie – Enveloped viruses, Vectors and Immuno-therapy (EVIR), Centre International de Recherche en Infectiologie - UMR (CIRI), École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Virus, mmunité innée et trafic vésiculaire - Vesicular trafficking, innate response and viruses (VIV), Centre de Recherche Saint-Antoine (CR Saint-Antoine), Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre d'Immunologie et des Maladies Infectieuses (CIMI), Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Research Unit on Cardiovascular and Metabolic Diseases [IHU ICAN], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Institut de Cardiométabolisme et Nutrition = Institute of Cardiometabolism and Nutrition [CHU Pitié Salpêtrière] (IHU ICAN), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre de Recherche Saint-Antoine (CRSA), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Mère et enfant en milieu tropical : pathogènes, système de santé et transition épidémiologique (MERIT - UMR_D 216), Institut de Recherche pour le Développement (IRD)-Université de Paris (UP), Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Institute of cardiometabolism and nutrition (ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Trafic Vésiculaire, Réponse Innée et Virus – Vesicular trafficking, Innate response, Mère et enfant en milieu tropical : pathogènes, système de santé et transition épidémiologique (MERIT - UMR_D 261), Institut de Recherche pour le Développement (IRD)-Université Paris Cité (UPCité), Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Research Unit on Cardiovascular and Metabolic Diseases (ICAN), Centre International de Recherche en Infectiologie (CIRI), École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), ANR-16-CE15-0004,MALINV,Identification des facteurs de virulence de Plasmodium impliqués dans l'invasion des hépatocytes(2016), and Gestionnaire, Hal Sorbonne Université

Subjects
CD36 Antigens, Models, Molecular, Plasmodium, [SDV]Life Sciences [q-bio], lcsh:R, lcsh:Medicine, Article, Tetraspanin 28, Malaria, Parasite biology, Mice, Protein Domains, Sporozoites, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, parasitic diseases, [SDV.MHEP.MI] Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Hepatocytes, Animals, Humans, lcsh:Q, [SDV.MP.PAR]Life Sciences [q-bio]/Microbiology and Parasitology/Parasitology, Amino Acid Sequence, lcsh:Science, [SDV.MP.PAR] Life Sciences [q-bio]/Microbiology and Parasitology/Parasitology
Abstract

International audience; Sporozoite forms of the Plasmodium parasite, the causative agent of malaria, are transmitted by mosquitoes and first infect the liver for an initial round of replication before parasite proliferation in the blood. The molecular mechanisms involved during sporozoite invasion of hepatocytes remain poorly understood. Two receptors of the Hepatitis C virus (HCV), the tetraspanin CD81 and the scavenger receptor class B type 1 (SR-B1), play an important role during the entry of Plasmodium sporozoites into hepatocytes. In contrast to HCV entry, which requires both CD81 and SR-B1 together with additional host factors, CD81 and SR-B1 operate independently during malaria liver infection. Sporozoites from human-infecting P. falciparum and P. vivax rely respectively on CD81 or SR-B1. Rodent-infecting P. berghei can use SR-B1 to infect host cells as an alternative pathway to CD81, providing a tractable model to investigate the role of SR-B1 during Plasmodium liver infection. Here we show that mouse SR-B1 is less functional as compared to human SR-B1 during P. berghei infection. We took advantage of this functional difference to investigate the structural determinants of SR-B1 required for infection. Using a structure-guided strategy and chimeric mouse/human SR-B1 constructs, we could map the functional region of human SR-B1 within apical loops, suggesting that this region of the protein may play a crucial role for interaction of sporozoite ligands with host cells and thus the very first step of Plasmodium infection.

Published
2020
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2. Adipocyte ATP-Binding Cassette Gal Promotes Triglyceride Storage, Fat Mass Growth, and Human Obesity

Author

Frisdal, Eric, Le Lay, Soazig, Hooton, Henri, Poupel, Lucie, Olivier, Maryline, Alili, Rohia, Plengpanich, Wanee, Villard, Elise F., Gilibert, Sophie, Lhomme, Marie, Superville, Alexandre, Miftah-Alkhair, Lobna, Chapman, M. John, Dallinga-Thie, Geesje M., Venteclef, Nicolas, Poitou, Christine, Tordjman, Joan, Lesnik, Philippe, Kontush, Anatol, Huby, Thierry, Dugail, Isabelle, Clement, Karine, Guerin, Maryse, Le Goff, Wilfried, Amsterdam Cardiovascular Sciences, and Vascular Medicine

Subjects
lipids (amino acids, peptides, and proteins)
Abstract

The role of the ATP-binding cassette G1 (ABCG1) transporter in human pathophysiology is still largely unknown. Indeed, beyond its role in mediating free cholesterol efflux to HDL, the ABCG1 transporter equally promotes lipid accumulation in a triglyceride (TG)-rich environment through regulation of the bioavailability of lipoprotein lipase (LPL). Because both ABCG1 and LPL are expressed in adipose tissue, we hypothesized that ABCG1 is implicated in adipocyte TG storage and therefore could be a major actor in adipose tissue fat accumulation. Silencing of Abcg1 expression by RNA interference in 3T3-L1 preadipocytes compromised LPL-dependent TG accumulation during the initial phase of differentiation. Generation of stable Abcg1 knockdown 3T3-L1 adipocytes revealed that Abcg1 deficiency reduces TG storage and diminishes lipid droplet size through inhibition of Ppar expression. Strikingly, local inhibition of adipocyte Abcg1 in adipose tissue from mice fed a high-fat diet led to a rapid decrease of adiposity and weight gain. Analysis of two frequent ABCG1 single nucleotide polymorphisms (rs1893590 [A/C] and rs1378577 [T/G]) in morbidly obese individuals indicated that elevated ABCG1 expression in adipose tissue was associated with increased PPAR expression and adiposity concomitant to increased fat mass and BMI (haplotype AT>GC). The critical role of ABCG1 in obesity was further confirmed in independent populations of severe obese and diabetic obese individuals. This study identifies for the first time a major role of adipocyte ABCG1 in adiposity and fat mass growth and suggests that adipose ABCG1 might represent a potential therapeutic target in obesity

Published
2015

3. Differential regulation of the human versus the mouse apolipoprotein AV gene by PPARalpha Implications for the study of pharmaceutical modifiers of hypertriglyceridemia in mice

Author

Prieur, Xavier, Lesnik, Philipp, Moreau, Martine, Rodríguez Rubio, Joan Carles, Doucet, Chantal, Chapman, M. John, Huby, Thierry, and Universitat de Barcelona

Subjects
Apolipoproteins, Triglicèrids, Apoproteïnes, Gene expression, Expressió gènica, Triglycerides
Abstract

Mice have been used widely to define the mechanism of action of fibric acid derivatives. The fibrates are pharmacological agonists of the peroxisome proliferator-activated receptor α (PPARα), whose activation in human subjects promotes potent reduction in plasma levels of triglycerides (TG) with concomitant increase in those of HDL-cholesterol. The impact of PPARα agonists on gene expression in humans and rodents is however distinct; such distinctions include differential regulation of key genes of lipid metabolism. We evaluated the question as to whether the human and murine genes encoding apolipoprotein apoAV, a regulator of plasma concentrations of TG-rich lipoproteins, might be differentially regulated in response to fibrates. Fenofibrate, a classic PPARα agonist, repressed expression of mouse Apoa5 in vivo in a mouse model transgenic for the human APOA5 gene; by contrast, expression of the human ortholog was up-regulated. Our findings are consistent with the presence of a functional PPAR-binding element in the promoter of the human APOA5 gene; this element is however degenerate and non-functional in the corresponding mouse Apoa5 sequence, as demonstrated by reporter assays and gel shift analyses. These data further highlights the distinct mechanisms which are implicated in the metabolism of TG-rich lipoproteins in mice as compared to man. They equally emphasize the importance of the choice of a mouse model for investigation of the impact of pharmaceutical modifiers on hypertriglyceridemia.

Published
2009

5. Plasmodium P36 determines host cell receptor usage during sporozoite invasion

Author

Manzoni, Giulia, Marinach, Carine, Topçu, Selma, Briquet, Sylvie, Grand, Morgane, Tolle, Matthieu, Gransagne, Marion, Lescar, Julien, Andolina, Chiara, Franetich, Jean-François, Zeisel, Mirjam B, Huby, Thierry, Rubinstein, Eric, Snounou, Georges, Mazier, Dominique, Nosten, François, Baumert, Thomas F, Silvie, Olivier, Centre d'Immunologie et de Maladies Infectieuses (CIMI), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC), Nuffield (Nuffield), University of Oxford [Oxford], Shoklo Malaria Research Unit [Mae Sot, Thailand] (SMRU), Mahidol Oxford Tropical Medicine Research Unit (MORU), Wellcome Trust-Mahidol University [Bangkok]-University of Oxford [Oxford]-Wellcome Trust-Mahidol University [Bangkok]-University of Oxford [Oxford], Interactions Virus-Hôte et Maladies Hépatiques, Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Virologie, Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Institute of cardiometabolism and nutrition (ICAN), Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Modèles de Cellules Souches Malignes et Thérapeutiques, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Sud - Paris 11 (UP11), Institut André Lwoff - Biologie intégrée de la cellule, virus et cancer (IALBICVC), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris-Sud - Paris 11 (UP11), CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service d'Hépatogastroentérologie, Les Hôpitaux Universitaires de Strasbourg (HUS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), University of Oxford, University of Oxford-Mahidol University [Bangkok]-Wellcome Trust-University of Oxford-Mahidol University [Bangkok]-Wellcome Trust, Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Research Unit on Cardiovascular and Metabolic Diseases (ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Université Paris-Sud - Paris 11 (UP11)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris-Sud - Paris 11 (UP11)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), and HAL UPMC, Gestionnaire

Subjects
Plasmodium, Mouse, QH301-705.5, Science, malaria, P. berghei, P. falciparum, Host-Parasite Interactions, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, parasitic diseases, hepatocyte, Animals, sporozoite, P. vivax, Parasites, [SDV.MP.PAR]Life Sciences [q-bio]/Microbiology and Parasitology/Parasitology, Biology (General), Microbiology and Infectious Disease, P. yoelii, Sporozoites, [SDV.MHEP.MI] Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Hepatocytes, Medicine, Other, [SDV.MP.PAR] Life Sciences [q-bio]/Microbiology and Parasitology/Parasitology, Research Article, Human
Abstract

Plasmodium sporozoites, the mosquito-transmitted forms of the malaria parasite, first infect the liver for an initial round of replication before the emergence of pathogenic blood stages. Sporozoites represent attractive targets for antimalarial preventive strategies, yet the mechanisms of parasite entry into hepatocytes remain poorly understood. Here we show that the two main species causing malaria in humans, Plasmodium falciparum and Plasmodium vivax, rely on two distinct host cell surface proteins, CD81 and the Scavenger Receptor BI (SR-BI), respectively, to infect hepatocytes. By contrast, CD81 and SR-BI fulfil redundant functions during infection by the rodent parasite P. berghei. Genetic analysis of sporozoite factors reveals the 6-cysteine domain protein P36 as a major parasite determinant of host cell receptor usage. Our data provide molecular insights into the invasion pathways used by different malaria parasites to infect hepatocytes, and establish a functional link between a sporozoite putative ligand and host cell receptors. DOI: http://dx.doi.org/10.7554/eLife.25903.001, eLife digest Malaria is an infectious disease that affects millions of people around the world and remains a major cause of death, especially in Africa. It is caused by Plasmodium parasites, which are transmitted by mosquitoes to mammals. Once in the mammal, the parasites infect liver cells, where they multiply. Previous studies have suggested that proteins on the surface of the liver cells and on the parasite affect how Plasmodium infects liver cells. Understanding how these proteins enable the parasites to enter the cells may help researchers to develop treatments that interrupt the parasite life cycle and prevent infection. Manzoni et al. have now investigated how different malaria parasite species interact with liver cells. The main parasite species that infect humans are Plasmodium falciparum in Africa and Plasmodium vivax outside Africa. Manzoni et al. found that P. falciparum and P. vivax infect human liver cells by two different routes: P. falciparum interacts with a liver cell protein called CD81, and P. vivax interacts with a liver cell protein called SR-BI. Further experiments that used mutant forms of malaria parasites that infect mice showed that a parasite protein called P36 determines which liver cell protein the parasite will interact with. The next step is to understand how P36 interacts with the liver cell proteins and to identify other parasite proteins that help Plasmodium to invade cells. In the future, such knowledge may help to develop a highly effective malaria vaccine. DOI: http://dx.doi.org/10.7554/eLife.25903.002

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6. Targeted invalidation of SR-B1 in macrophages reduces macrophage apoptosis and accelerates atherosclerosis

Author

Wilfried Le Goff, Raphaëlle Ballaire, Fulvia Troise, Martine Moreau, Lucie Poupel, Philippe Lesnik, Francesco Potì, Thomas Huby, Emanuele Sasso, Emmanuel L. Gautier, Thierry Huby, Lauriane Galle-Treger, Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Institute of cardiometabolism and nutrition (ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Università degli studi di Napoli Federico II, University of Parma = Università degli studi di Parma [Parme, Italie], Galle-Treger, Lauriane, Moreau, Martine, Ballaire, Raphaëlle, Poupel, Lucie, Huby, Thoma, Sasso, Emanuele, Troise, Fulvia, Poti, Francesco, Lesnik, Philippe, Le Goff, Wilfried, Gautier, Emmanuel L, and Huby, Thierry

Subjects
THP-1 Cell, Apoptosis Inhibitor, Physiology, THP-1 Cells, Macrophage, [SDV]Life Sciences [q-bio], Apoptosis, 030204 cardiovascular system & hematology, SR-B1, 0302 clinical medicine, Aorta, Bone Marrow Transplantation, Mice, Knockout, Receptors, Scavenger, 0303 health sciences, Apoptosis Regulatory Protein, biology, Chemistry, Scavenger Receptors, Class B, Plaque, Atherosclerotic, Haematopoiesis, medicine.anatomical_structure, Cholesterol, Atherosclerosi, Disease Progression, Cardiology and Cardiovascular Medicine, Human, Signal Transduction, STAT3 Transcription Factor, Aortic Diseases, 03 medical and health sciences, In vivo, Physiology (medical), Cholesterylester transfer protein, medicine, Animals, Humans, 030304 developmental biology, Animal, Monocyte, Macrophages, Apoptosi, Aortic Disease, Atherosclerosis, Molecular biology, Mice, Inbred C57BL, Disease Models, Animal, Receptors, LDL, biology.protein, Bone marrow, Apoptosis Regulatory Proteins
Abstract

Aims SR-B1 is a cholesterol transporter that exerts anti-atherogenic properties in liver and peripheral tissues in mice. Bone marrow (BM) transfer studies suggested an atheroprotective role in cells of haematopoietic origin. Here, we addressed the specific contribution of SR-B1 in the monocyte/macrophage. Methods and results We generated mice deficient for SR-B1 in monocytes/macrophages (Lysm-Cre × SR-B1f/f) and transplanted their BM into Ldlr−/− mice. Fed a cholesterol-rich diet, these mice displayed accelerated aortic atherosclerosis characterized by larger macrophage-rich areas and decreased macrophage apoptosis compared with SR-B1f/f transplanted controls. These findings were reproduced in BM transfer studies using another atherogenic mouse recipient (SR-B1 KOliver × Cholesteryl Ester Transfer Protein). Haematopoietic reconstitution with SR-B1−/− BM conducted in parallel generated similar results to those obtained with Lysm-Cre × SR-B1f/f BM; thus suggesting that among haematopoietic-derived cells, SR-B1 exerts its atheroprotective role primarily in monocytes/macrophages. Consistent with our in vivo data, free cholesterol (FC)-induced apoptosis of macrophages was diminished in the absence of SR-B1. This effect could not be attributed to differential cellular cholesterol loading. However, we observed that expression of apoptosis inhibitor of macrophage (AIM) was induced in SR-B1-deficient macrophages, and notably upon FC-loading. Furthermore, we demonstrated that macrophages were protected from FC-induced apoptosis by AIM. Finally, AIM protein was found more present within the macrophage-rich area of the atherosclerotic lesions of SR-B1-deficient macrophages than controls. Conclusion Our findings suggest that macrophage SR-B1 plays a role in plaque growth by controlling macrophage apoptosis in an AIM-dependent manner.

Published
2020
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