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1. The impact of targeted malaria elimination with mass drug administrations on falciparum malaria in Southeast Asia: a cluster randomised trial

Author

Von Seidlein, L, Peto, TJ, Landier, J, Nguyen, T-N, Tripura, R, Phommasone, K, Pongvongsa, T, Lwin, KM, Keereecharoen, L, Kajeechiwa, L, Thwin, MM, Parker, DM, Wiladphaingern, J, Nosten, S, Proux, S, Corbel, V, Tuong-Vy, N, Phuc-Nhi, TL, Son, DH, Huong-Thu, PN, Tuyen, NTK, Tien, NT, Dong, LT, Hue, DV, Quang, HH, Nguon, C, Davoeung, C, Rekol, H, Adhikari, B, Henriques, G, Phongmany, P, Suangkanarat, P, Jeeyapant, A, Vihokhern, B, Van Der Pluijm, RW, Lubell, Y, White, LJ, Aguas, R, Promnarate, C, Sirithiranont, P, Malleret, B, Rénia, L, Onsjö, C, Chan, XH, Chalk, J, Miotto, O, Patumrat, K, Chotivanich, K, Hanboonkunupakarn, B, Jittmala, P, Kaehler, N, Cheah, PY, Pell, C, Dhorda, M, Imwong, M, Snounou, G, Mukaka, M, Peerawaranun, P, Lee, SJ, Simpson, JA, Pukrittayakamee, S, Singhasivanon, P, Grobusch, MP, Cobelens, F, Smithuis, F, Newton, PN, Thwaites, GE, Day, NPJ, Mayxay, M, Hien, TT, Nosten, FH, Dondorp, AM, White, NJ, Mahidol Oxford Tropical Medicine Research Unit (MORU), University of Oxford-Mahidol University [Bangkok]-Wellcome Trust, Centre for Tropical Medicine and Global Health [Oxford, UK], Nuffield Department of Medicine [Oxford, UK] (Big Data Institute), University of Oxford-University of Oxford, Sciences Economiques et Sociales de la Santé & Traitement de l'Information Médicale (SESSTIM - U1252 INSERM - Aix Marseille Univ - UMR 259 IRD), Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Shoklo Malaria Research Unit [Mae Sot, Thailand] (SMRU), University of Oxford-Mahidol University [Bangkok]-Wellcome Trust-University of Oxford-Mahidol University [Bangkok]-Wellcome Trust, Oxford University Clinical Research Unit [Ho Chi Minh City] (OUCRU), Department of Infectious Diseases [Amsterdam, Netherlands] (Academic Medical Center), University of Amsterdam [Amsterdam] (UvA)-Center for Tropical and Travel Medicine [Amsterdam, Netherlands], Lao-Oxford-Mahosot Hospital-Wellcome Trust Research Unit (LOMWRU), Mahidol University [Bangkok]-Mahosot Hospital, Amsterdam Institute for Global Health & Development [Amsterdam, The Netherlands], Savannakhet Provincial Health Department [Lao People’s Democratic Republic], Savannakhet Province [Lao People’s Democratic Republic], Department of Clinical Tropical Medicine [Bangkok, Thailand] (Faculty of Tropical Medicine), Mahidol University [Bangkok], Department of Population Health and Disease Prevention [Irvine, CA, USA], University of California [Irvine] (UC Irvine), University of California (UC)-University of California (UC), Génétique et évolution des maladies infectieuses (GEMI), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD [France-Sud]), Institute of Malariology, Parasitology, and Entomology [Ho Chi Minh City, Vietnam] (IMPE), Center for Malariology, Parasitology and Entomology [Ninh Thuan Province, Vietnam] (CMPE), Institute of Malariology, Parasitology, and Entomology [Quy Nhon, Vietnam] (IMPE), National Center for Parasitology, Entomology and Malaria Control [Phnom Penh, Cambodia] (CNM), Provincial Health Department [Battambang, Cambodia] (PHD), Department of Pathogen Molecular Biology [London, UK], London School of Hygiene and Tropical Medicine (LSHTM), WWARN Asia Regional Centre [Bangkok, Thailand], Department of Microbiology & Immunology [Singapore] (Yong Loo Lin School of Medicine), National University of Singapore (NUS), Singapore Immunology Network (SIgN), Biomedical Sciences Institute (BMSI), Department of Oncology, Clinical and Experimental Medicine, Faculty of Health Sciences [Linköping University ], Linköping University (LIU), Wellcome Trust Sanger Institute [Hinxton, UK], Department of Molecular Tropical Medicine and Genetics [Bangkok, Thailand] (Faculty of Tropical Medicine), Department of Tropical Hygiene [Bangkok, Thailand] (Faculty of Tropical Medicine), Immunologie des Maladies Virales et Autoimmunes (IMVA - U1184), Université Paris-Sud - Paris 11 (UP11)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre for Epidemiology and Biostatistics [Victoria, Australia], University of Melbourne-Melbourne School of Population and Global Health [Victoria, Australia], Royal Society of Thailand [Bangkok, Thailand], Myanmar Oxford Clinical Research Unit [Yangon, Myanmar], Institute of Research and Education Development [Vientiane, Lao People’s Democratic Republic], University of Health Sciences [Vientiane, Laos] (UHS), NJW is the recipient of the Wellcome Trust Award Number: 101148/Z/13/Z. AMD is the recipient of the Bill and Melinda Gates Foundation Award Number: OPP1081420. JAS is the recipient of the National Health and Medical Research Council Award Number: 1104975., Dupuis, Christine, Mahidol Oxford Tropical Medicine Research Unit, University of Oxford [Oxford]-Mahidol University [Bangkok], University of Oxford [Oxford]-Mahidol University [Bangkok]-Wellcome Trust, Shoklo Malaria Research Unit [Mae Sot, Thailand] (Faculty of Tropical Medicine), Mahidol University [Bangkok]-Mahidol Oxford Tropical Medicine Research Unit (MORU), University of Oxford [Oxford]-Mahidol University [Bangkok]-Wellcome Trust-University of Oxford [Oxford]-Wellcome Trust, Laboratoire de Lutte contre les Insectes Nuisibles, National Institute of Malariology, Parasitology and Entomology, National Center for Parasitology, Entomology, and Malaria Control, Institut des Maladies Emergentes et des Thérapies Innovantes (IMETI), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay, Institut Cochin (UMR_S567 / UMR 8104), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5), Faculty of Tropical Medicine [Bangkok, Thailand], University of Oxford [Oxford], Faculty of Tropical Medicine, University of Oxford-Mahidol University [Bangkok], National Institute of Malariology, Parasitology and Entomology [Hanoi] (NIMPE), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), University of Oxford, Maladies infectieuses et vecteurs : écologie, génétique, évolution et contrôle (MIVEGEC), Wellcome Trust-Mahidol University [Bangkok]-University of Oxford [Oxford], Wellcome Trust-Mahidol University [Bangkok]-University of Oxford [Oxford]-Wellcome Trust-Mahidol University [Bangkok]-University of Oxford [Oxford], University of Oxford [Oxford]-University of Oxford [Oxford], University of California [Irvine] (UCI), University of California-University of California, Graduate School, AII - Infectious diseases, APH - Aging & Later Life, APH - Global Health, APH - Methodology, Global Health, Infectious diseases, APH - Health Behaviors & Chronic Diseases, and APH - Quality of Care

Subjects
Male, Plasmodium, Myanmar, Medical and Health Sciences, Geographical Locations, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Medicine and Health Sciences, Cluster Analysis, Malaria, Falciparum, Child, Asia, Southeastern, ComputingMilieux_MISCELLANEOUS, Cross-Over Studies, Pharmaceutics, Drugs, Drug Resistance, Multiple, Vietnam, [SDV.MHEP.MI] Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Medicine, Mass Drug Administration, Female, Cambodia, Research Article, Adult, Drug Administration, Asia, Adolescent, Elimination, Plasmodium falciparum, Microbiology, Antimalarials, Young Adult, Drug Therapy, Microbial Control, General & Internal Medicine, Parasite Groups, parasitic diseases, Parasitic Diseases, Humans, [SDV.MP.PAR]Life Sciences [q-bio]/Microbiology and Parasitology/Parasitology, Disease Eradication, Pharmacology, Biology and Life Sciences, Tropical Diseases, Malaria, [SDV.SPEE] Life Sciences [q-bio]/Santé publique et épidémiologie, People and Places, Parasitology, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, Antimicrobial Resistance, Apicomplexa
Abstract

Background The emergence and spread of multidrug-resistant Plasmodium falciparum in the Greater Mekong Subregion (GMS) threatens global malaria elimination efforts. Mass drug administration (MDA), the presumptive antimalarial treatment of an entire population to clear the subclinical parasite reservoir, is a strategy to accelerate malaria elimination. We report a cluster randomised trial to assess the effectiveness of dihydroartemisinin-piperaquine (DP) MDA in reducing falciparum malaria incidence and prevalence in 16 remote village populations in Myanmar, Vietnam, Cambodia, and the Lao People’s Democratic Republic, where artemisinin resistance is prevalent. Methods and findings After establishing vector control and community-based case management and following intensive community engagement, we used restricted randomisation within village pairs to select 8 villages to receive early DP MDA and 8 villages as controls for 12 months, after which the control villages received deferred DP MDA. The MDA comprised 3 monthly rounds of 3 daily doses of DP and, except in Cambodia, a single low dose of primaquine. We conducted exhaustive cross-sectional surveys of the entire population of each village at quarterly intervals using ultrasensitive quantitative PCR to detect Plasmodium infections. The study was conducted between May 2013 and July 2017. The investigators randomised 16 villages that had a total of 8,445 residents at the start of the study. Of these 8,445 residents, 4,135 (49%) residents living in 8 villages, plus an additional 288 newcomers to the villages, were randomised to receive early MDA; 3,790 out of the 4,423 (86%) participated in at least 1 MDA round, and 2,520 out of the 4,423 (57%) participated in all 3 rounds. The primary outcome, P. falciparum prevalence by month 3 (M3), fell by 92% (from 5.1% [171/3,340] to 0.4% [12/2,828]) in early MDA villages and by 29% (from 7.2% [246/3,405] to 5.1% [155/3,057]) in control villages. Over the following 9 months, the P. falciparum prevalence increased to 3.3% (96/2,881) in early MDA villages and to 6.1% (128/2,101) in control villages (adjusted incidence rate ratio 0.41 [95% CI 0.20 to 0.84]; p = 0.015). Individual protection was proportional to the number of completed MDA rounds. Of 221 participants with subclinical P. falciparum infections who participated in MDA and could be followed up, 207 (94%) cleared their infections, including 9 of 10 with artemisinin- and piperaquine-resistant infections. The DP MDAs were well tolerated; 6 severe adverse events were detected during the follow-up period, but none was attributable to the intervention. Conclusions Added to community-based basic malaria control measures, 3 monthly rounds of DP MDA reduced the incidence and prevalence of falciparum malaria over a 1-year period in areas affected by artemisinin resistance. P. falciparum infections returned during the follow-up period as the remaining infections spread and malaria was reintroduced from surrounding areas. Limitations of this study include a relatively small sample of villages, heterogeneity between villages, and mobility of villagers that may have limited the impact of the intervention. These results suggest that, if used as part of a comprehensive, well-organised, and well-resourced elimination programme, DP MDA can be a useful additional tool to accelerate malaria elimination. Trial registration ClinicalTrials.gov NCT01872702, In a cluster-randomized trial, Lorenz von Seidlin & colleagues investigate whether mass drug administration can accelerate malaria elimination in the Greater Mekong Subregion., Author summary Why was this study done? The emergence and spread of multidrug resistance in the Greater Mekong Subregion (GMS) threaten regional and global malaria control. Mass drug administrations (MDAs) are controversial but could be useful in the control and elimination of malaria. We wanted to know whether well-resourced MDAs can accelerate malaria elimination in the GMS. What did the researchers do and find? We randomised 16 villages (clusters) to receive MDAs with antimalarial drugs (dihydroartemisinin-piperaquine [DP] plus low-dose primaquine) either in year 1 or year 2 of the study. The entire village population (except pregnant women and children under the age of 6 months) was invited to take 3 consecutive daily doses of antimalarial drugs 3 times at monthly intervals. Everyone was followed up for 1 year; all malaria cases were recorded, and quarterly malaria surveys were conducted using highly sensitive high-volume PCR detection. Most (87%) of the villagers completed at least 1 round of the antimalarial drugs, which were well tolerated. The intervention had a substantial impact on the prevalence of P. falciparum infections by month 3 after the start of the MDAs. Over the subsequent 9 months, P. falciparum infections returned but stayed below baseline levels. What do these findings mean? MDAs might be a useful tool to accelerate falciparum malaria elimination in low-endemicity settings. The effectiveness of MDAs depends on continued support for village health workers, adequate drug efficacy, high levels of community participation, and carefully planned roll out to minimise the risk of malaria reintroduction.

Published
2019
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2. Single-Cell Analysis of Human Mononuclear Phagocytes Reveals Subset-Defining Markers and Identifies Circulating Inflammatory Dendritic Cells

Author

Dutertre, C.-A. Becht, E. Irac, S.E. Khalilnezhad, A. Narang, V. Khalilnezhad, S. Ng, P.Y. van den Hoogen, L.L. Leong, J.Y. Lee, B. Chevrier, M. Zhang, X.M. Yong, P.J.A. Koh, G. Lum, J. Howland, S.W. Mok, E. Chen, J. Larbi, A. Tan, H.K.K. Lim, T.K.H. Karagianni, P. Tzioufas, A.G. Malleret, B. Brody, J. Albani, S. van Roon, J. Radstake, T. Newell, E.W. Ginhoux, F.

Abstract

Human mononuclear phagocytes comprise phenotypically and functionally overlapping subsets of dendritic cells (DCs) and monocytes, but the extent of their heterogeneity and distinct markers for subset identification remains elusive. By integrating high-dimensional single-cell protein and RNA expression data, we identified distinct markers to delineate monocytes from conventional DC2 (cDC2s). Using CD88 and CD89 for monocytes and HLA-DQ and FcεRIα for cDC2s allowed for their specific identification in blood and tissues. We also showed that cDC2s could be subdivided into phenotypically and functionally distinct subsets based on CD5, CD163, and CD14 expression, including a distinct subset of circulating inflammatory CD5−CD163+CD14+ cells related to previously defined DC3s. These inflammatory DC3s were expanded in systemic lupus erythematosus patients and correlated with disease activity. These findings further unravel the heterogeneity of DC subpopulations in health and disease and may pave the way for the identification of specific DC subset-targeting therapies. Using high-dimensional protein and RNA single-cell analyses, Dutertre et al. analyze human dendritic cell and monocyte subsets and identify markers that delineate them and unravel their heterogeneity. They also reveal the presence of inflammatory CD14+ DC3s, a subset of cDC2s, that correlate with disease progression and may be functionally involved in systemic lupus erythematosus immunopathology. © 2019 Elsevier Inc.

Published
2019

3. Monocyte subsets have distinct patterns of tetraspanin expression and different capacities to form multinucleate giant cells

Author

Champion, T.C., Partridge, L.J., Ong, S.-M., Malleret, B., Wong, S.-C., and Monk, P.N.

Abstract

Monocytes are able to undergo homotypic fusion to produce different types of multinucleated giant cells, such as Langhans giant cells in response to M. tuberculosis infection or foreign body giant cells in response to implanted biomaterials. Monocyte fusion is highly coordinated and complex, with various soluble, intracellular, and cell-surface components mediating different stages of the process. Tetraspanins, such as CD9, CD63, and CD81, are known to be involved in cell:cell fusion and have been suggested to play a role in regulating homotypic monocyte fusion. However, peripheral human monocytes are not homogenous: they exist as a heterogeneous population consisting of three subsets, classical (CD14++CD16−), intermediate (CD14++CD16+), and non-classical (CD14+CD16+), at steady state. During infection with mycobacteria, the circulating populations of intermediate and non-classical monocytes increase, suggesting they may play a role in the disease outcome. Human monocytes were separated into subsets and then induced to fuse using concanavalin A. The intermediate monocytes were able to fuse faster and form significantly larger giant cells than the other subsets. When antibodies targeting tetraspanins were added, the intermediate monocytes responded to anti-CD63 by forming smaller giant cells, suggesting an involvement of tetraspanins in fusion for at least this subset. However, the expression of fusion-associated tetraspanins on monocyte subsets did not correlate with the extent of fusion or with the inhibition by tetraspanin antibody. We also identified a CD9High and a CD9Low monocyte population within the classical subset. The CD9High classical monocytes expressed higher levels of tetraspanin CD151 compared to CD9Low classical monocytes but the CD9High classical subset did not exhibit greater potential to fuse and the role of these cells in immunity remains unknown. With the exception of dendrocyte-expressed seven transmembrane protein, which was expressed at higher levels on the intermediate monocyte subset, the expression of fusion-related proteins between the subsets did not clearly correlate with their ability to fuse. We also did not observe any clear correlation between giant cell formation and the expression of pro-inflammatory or fusogenic cytokines. Although tetraspanin expression appears to be important for the fusion of intermediate monocytes, the control of multinucleate giant cell formation remains obscure.

Published
2018

4. Breadth of humoral response and antigenic targets of sporozoite-inhibitory antibodies associated with sterile protection induced by controlled human malaria infection

Author

Peng, K., Goh, Y.S., Siau, A., Franetich, J.F., Chia, W.N., Ong, A.S., Malleret, B., Wu, Y.Y., Snounou, G., Hermsen, C.C., Adams, J.H., Mazier, D., Preiser, P.R., Sauerwein, R.W., Grüner, A.C., and Rénia, L.

Subjects
lnfectious Diseases and Global Health Radboud Institute for Molecular Life Sciences [Radboudumc 4]
Abstract

Contains fulltext : 172042.pdf (Publisher’s version ) (Closed access)

Published
2016

5. Physiopathologie de l’infection à Chikungunya : infection expérimentale du macaque par la souche ChikV OPY1 isolée d’un patient réunionnais

Author

Roques, Pierre, Joubert, Christophe, Malleret, B, Delache, B, Brochard, P, Calvo, Javier, Morin, J, Mannioui, A, Martinon, F, Lebon, P, Verrier, B, Lotteau, V, de Lamballerie, X, Cherel, Yan, Larcher, Thibaut, Aumont, Gilles, Le Grand, R, Inconnu, Développement et Pathologie du Tissu Musculaire (DPTM), Institut National de la Recherche Agronomique (INRA)-Ecole Nationale Vétérinaire de Nantes, Département Santé Animale (DEPT SA), Institut National de la Recherche Agronomique (INRA), and ProdInra, Migration

Subjects
[SDV] Life Sciences [q-bio], [SDV]Life Sciences [q-bio]
Published
2007

6. Physiopathologie de l'infection à Chikungunya : infection expérimentale du macaque par le virus de la Réunion ChikV OPY1

Author

Roques, Pierre, Malleret, B, Joubert, Christophe, Delache, B, Brochard, P, Calvo, Javier, Picq, I, Mannioui, K, Martinon, F, Lebon, P, de Lamballerie, X, Verrier, B, Prevot, S, Cherel, Yan, Aumont, Gilles, Le Grand, R, Inconnu, Développement et Pathologie du Tissu Musculaire (DPTM), Institut National de la Recherche Agronomique (INRA)-Ecole Nationale Vétérinaire de Nantes, Département Santé Animale (DEPT SA), Institut National de la Recherche Agronomique (INRA), and ProdInra, Migration

Subjects
[SDV] Life Sciences [q-bio], [SDV]Life Sciences [q-bio], ComputingMilieux_MISCELLANEOUS
Abstract

National audience

Published
2007

7. Chikungunya Reunion outbreak: experimental infection of macaques as a model of the acute pathology

Author

Roques, Pierre, Joubert, Christophe, Malleret, B, Delache, B, Brochard, P, Mannioui, A, Martinon, F, Lebon, P, Verrier, B, Lotteau, V, de Lamballerie, X, Cherel, Yan, Larcher, Thibaut, Aumont, Gilles, Le Grand, R, Inconnu, Développement et Pathologie du Tissu Musculaire (DPTM), Institut National de la Recherche Agronomique (INRA)-Ecole Nationale Vétérinaire de Nantes, Département Santé Animale (DEPT SA), Institut National de la Recherche Agronomique (INRA), and ProdInra, Migration

Subjects
[SDV] Life Sciences [q-bio], [SDV]Life Sciences [q-bio], ComputingMilieux_MISCELLANEOUS
Abstract

International audience

Published
2007

8. Strict tropism for CD71+/ CD234+ human reticulocytes limits Plasmodium cynomolgi's zoonotic potential

Author

Kosaisavee, V, Suwanarusk, R, Chua, A, Kyle, D, Malleret, B, Zhang, R, Imwong, M, Imerbsin, R, Ubalee, R, Sámano-Sánchez, H, Yeung, B, Ong, J, Lombardini, E, Nosten, F, Tan, K, Bifani, P, Snounou, G, Rénia, L, and Russell, B

Subjects
parasitic diseases
Abstract

Two malaria parasites of Southeast Asian macaques, Plasmodium knowlesi and P. cynomolgi, can infect humans experimentally. In Malaysia, where both species are common, zoonotic knowlesi malaria has recently become dominant, and cases are recorded throughout the region. By contrast, to date only a single case of naturally acquired P. cynomolgi has been found in humans. In this study we show that whereas P. cynomolgi merozoites invade monkey red blood cells (RBCs) indiscriminately in vitro, for humans they are restricted to reticulocytes expressing both transferrin receptor 1 (Trf1 or CD71) and the Duffy antigen/chemokine receptor (DARC or CD234). This likely contributes to the paucity of detectable zoonotic cynomolgi malaria. We further describe post-invasion morphological and rheological alterations in P. cynomolgi-infected human reticulocytes that are strikingly similar to those observed for P. vivax These observations stress the value of P. cynomolgi as a model in the development of blood stage vaccines against vivax malaria.

9. A subset of Kupffer cells regulates metabolism through the expression of CD36

Author

Guochen Wan, Nicholas Ang, Shanshan W. Howland, Svetoslav Chakarov, Evan W. Newell, Gregoire Gessain, Wan Ting Kong, Cecilia Morgantini, Olivier N. F. Cexus, Bernett Lee, Zhaoyuan Liu, Xenia Ficht, Ping Chen, Giorgia De Simone, Emelie Barreby, Josephine Lum, Nicolas Venteclef, Francesco Andreata, Ahad Khalilnezhad, Myriam Aouadi, Jinmiao Chen, Connie Xu, Xiaomeng Zhang, Ivy Low, Foo Shihui, Garett Dunsmore, Anis Larbi, Laurent Yvan-Charvet, Camille Blériot, Wei Guo, Rhea Pai, Muhammad Faris Bin Mohd Kairi, Benoit Malleret, Radoslaw M. Sobota, Wint Wint Phoo, Florent Ginhoux, Lai Guan Ng, Valerio Azzimato, Marc Bajénoff, Raphaelle Ballaire, Matteo Iannacone, Valeria Fumagalli, Ankur Sharma, Akhila Balachander, Singapore Immunology Network (SIgN), Biomedical Sciences Institute (BMSI), Karolinska Institute, Institut Gustave Roussy (IGR), Immunologie anti-tumorale et immunothérapie des cancers (ITIC), Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Inovarion, IRCCS San Raffaele Scientific Institute [Milan, Italie], Universita Vita Salute San Raffaele = Vita-Salute San Raffaele University [Milan, Italie] (UniSR), Equipe Electronique - Laboratoire GREYC - UMR6072, Groupe de Recherche en Informatique, Image et Instrumentation de Caen (GREYC), Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-École Nationale Supérieure d'Ingénieurs de Caen (ENSICAEN), Normandie Université (NU)-Centre National de la Recherche Scientifique (CNRS)-Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Centre National de la Recherche Scientifique (CNRS), Karolinska Institutet [Stockholm], Shangaï Jiao Tong University [Shangaï], Genome Institute of Singapore (GIS), National University of Singapore (NUS), University of Surrey (UNIS), Agency for science, technology and research [Singapore] (A*STAR), Aix Marseille Université (AMU), Centre méditerranéen de médecine moléculaire (C3M), Université Nice Sophia Antipolis (1965 - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Côte d'Azur (UCA), Immunité et métabolisme dans le diabète = IMmunity and MEtabolism in DIABetes [CRC] (IMMEDIAB Lab), Centre de Recherche des Cordeliers (CRC (UMR_S_1138 / U1138)), École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université Paris Cité (UPCité)-École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université Paris Cité (UPCité), Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS San Raffaele Pisana), Shanghai Jiao Tong University [Shanghai], Clinical Research Center, Department of Laboratory Medicine, Karolinska Institutet, Karolinska University Hospital Huddinge, Huddinge, Sweden, Karolinska Institutet [Stockholm]-Karolinska University Hospital [Stockholm], Inserm Avenir Group, Institut National de la Santé et de la Recherche Médicale (INSERM), Centre d'Immunologie de Marseille - Luminy (CIML), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), INSERM U1015, Unit of Immunology, Rheumatology, Allergy and Rare diseases, Milan (IRCCS San Raffaele Scientific Institute), E-institute of Shanghai University Immunology Division, Shanghai University, University of Surrey, - Biosciences and Medicine, Faculty of Health and Medical Sciences, Guildford, SingMass National Laboratory - Singapore, Bleriot, C., Barreby, E., Dunsmore, G., Ballaire, R., Chakarov, S., Ficht, X., De Simone, G., Andreata, F., Fumagalli, V., Guo, W., Wan, G., Gessain, G., Khalilnezhad, A., Zhang, X. M., Ang, N., Chen, P., Morgantini, C., Azzimato, V., Kong, W. T., Liu, Z., Pai, R., Lum, J., Shihui, F., Low, I., Xu, C., Malleret, B., Kairi, M. F. M., Balachander, A., Cexus, O., Larbi, A., Lee, B., Newell, E. W., Ng, L. G., Phoo, W. W., Sobota, R. M., Sharma, A., Howland, S. W., Chen, J., Bajenoff, M., Yvan-Charvet, L., Venteclef, N., Iannacone, M., Aouadi, M., Ginhoux, F., Bleriot, C, Barreby, E, Dunsmore, G, Ballaire, R, Chakarov, S, Ficht, X, De Simone, G, Andreata, F, Fumagalli, V, Guo, W, Wan, G, Gessain, G, Khalilnezhad, A, Zhang, X, Ang, N, Chen, P, Morgantini, C, Azzimato, V, Kong, W, Liu, Z, Pai, R, Lum, J, Shihui, F, Low, I, Xu, C, Malleret, B, Kairi, M, Balachander, A, Cexus, O, Larbi, A, Lee, B, Newell, E, Ng, L, Phoo, W, Sobota, R, Sharma, A, Howland, S, Chen, J, Bajenoff, M, Yvan-Charvet, L, Venteclef, N, Iannacone, M, Aouadi, M, Ginhoux, F, and Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Aix Marseille Université (AMU)

Subjects
CD36 Antigens, Kupffer Cells, CD36, [SDV]Life Sciences [q-bio], Immunology, Population, Kupffer cell, macrophage, liver, 03 medical and health sciences, chemistry.chemical_compound, Mice, 0302 clinical medicine, Immune system, scRNA-seq, medicine, Immunology and Allergy, Gene silencing, Macrophage, Animals, Obesity, education, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, 0303 health sciences, education.field_of_study, biology, Fatty acid metabolism, high fat diet, medicine.disease, Phenotype, Cell biology, macrophages, single cell, Oxidative Stress, Infectious Diseases, chemistry, CD206, Liver, 030220 oncology & carcinogenesis, biology.protein, Steatosis, heterogeneity, metabolism
Abstract

Tissue macrophages are immune cells whose phenotypes and functions are dictated by origin and niches. However, tissues are complex environments, and macrophage heterogeneity within the same organ has been overlooked so far. Here, we used high-dimensional approaches to characterize macrophage populations in the murine liver. We identified two distinct populations among embryonically derived Kupffer cells (KCs) sharing a core signature while differentially expressing numerous genes and proteins: a major CD206loESAM– population (KC1) and a minor CD206hiESAM+ population (KC2). KC2 expressed genes involved in metabolic processes, including fatty acid metabolism both in steady-state and in diet-induced obesity and hepatic steatosis. Functional characterization by depletion of KC2 or targeted silencing of the fatty acid transporter Cd36 highlighted a crucial contribution of KC2 in the liver oxidative stress associated with obesity. In summary, our study reveals that KCs are more heterogeneous than anticipated, notably describing a subpopulation wired with metabolic functions.

Published
2021
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10. Immunological history governs human stem cell memory CD4 heterogeneity via the Wnt signaling pathway

Author

Ezequiel Ruiz-Mateos, Naomi Mc Govern, Bernett Lee, Tamas Fulop, Karolina Pilipow, Tze Pin Ng, Crystal Tze Ying Tan, Shu Wen Tan, Reena Rajasuriar, Hartmut Geiger, Wilson How, Mai Chan Lau, Benoit Malleret, Amanda Amoah, Florent Ginhoux, Marie Strickland, Jin Miao Chen, Maria Carolina Florian, Glenn Wong, Enrico Lugli, Adeeba Kamarulzaman, Marion Chevrier, Veronica Zanon, Hassen Kared, Anis Larbi, Josephine Lum, [Kared,H, Tan,SW, Lau,MC, Chevrier,M, Tan,C, How,W, Wong,G, Strickland,M, Malleret,B, Govern,NM, Lum,J, Chen,JM, Lee,B, Ginhoux,F, Larbi,A] Singapore Immunology Network (SIgN), Agency for Science Technology and Research (A*STAR), Immunos Building, Biopolis, Republic of Singapore. [Strickland,M] Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton, UK. [Malleret,B, Larbi,A] Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Republic of Singapore. [Amoah,A, Florian,MC, Geiger,H] Institute of Molecular Medicine, University of Ulm, Ulm, Germany. [Pilipow,K, Zanon,V, Lugli,E] Humanitas Clinical and Research Center, Laboratory of Translational Immunology (LTI), Rozzano, Italy. [Geiger,H] Experimental Hematology and Cancer Biology, CCHMC, Cincinnati, OH, USA. [Ruiz-Mateos,E] Clinical Unit of Infectious Diseases, Microbiology and Preventive Medicine, Institute of Biomedicine of Seville (IBiS), Virgen del Rocío University Hospital, CSIC, University of Seville, Seville, Spain. [Fulop.T, Larbi,A] Department of Medicine, Faculty of Medicine, University of Sherbrooke, Sherbrooke, Quebec, Canada. [Rajasuriar,R, Kamarulzaman,A] Centre of Excellence for Research in AIDS (CERiA), University of Malaya, Kuala Lumpur, Malaysia. [Rajasuriar,R] The Peter Doherty Institute for Infection and Immunity, University of Melbourne, Melbourne, Victoria, Australia. [Rajasuriar,R, Kamarulzaman,A] Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia. [Ng,TP] Gerontology Research Programme and Department of Psychological Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore., The study is supported by a research grant from the Agency for Science, Technology and Research (No. 10-036), by the Singapore Immunology Network and by a Starting Grant from the European Research Council (ERC-StG-2014 PERSYST 640511 to E.L.). A.L. is a scholar of International Society for Advancement of Cytometry (ISAC). R.R. and A.K. are funded by the High Impact Research/Ministry of Higher Education Research Grant, Malaysia (HIR/ MOHE, H-20001-E000001) and the RU grant (UMRG RP029-14HTM). E.R-M was supported by Consejería de Salud y Bienestar Social of Junta de Andalucía through the Nicolás Monardes Program (C-0032/17) and Fondo de Investigación Sanitaria, Instituto de Salud Carlos III, Fondos Europeos para el Desarrollo Regional, FEDER, grants PI16/ 00684, PI19/01127, RETICS, Red de Investigación en SIDA (RD16/0025/0020)., Agency for Science, Technology and Research A*STAR (Singapore), Singapore Immunology Network, European Research Council, International Society for Advancement of Cytometry, Ministry of Higher Education (Malaysia), Junta de Andalucía, Instituto de Salud Carlos III, European Commission, and Red Española de Investigación en SIDA

Subjects
0301 basic medicine, CD4-Positive T-Lymphocytes, Aging, animal diseases, General Physics and Astronomy, HIV Infections, Signal transduction, Immunological memory, Memory T cells, Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Primates::Haplorhini::Catarrhini::Hominidae::Humans [Medical Subject Headings], Mice, 0302 clinical medicine, Organisms::Eukaryota::Animals [Medical Subject Headings], Cytotoxic T cell, Flow cytometry, lcsh:Science, Wnt Signaling Pathway, beta Catenin, Phenomena and Processes::Chemical Phenomena::Chemical Processes::Biochemical Processes::Signal Transduction::Wnt Signaling Pathway [Medical Subject Headings], Multidisciplinary, Wnt signaling pathway, Catenins, Chemicals and Drugs::Biological Factors::Intercellular Signaling Peptides and Proteins [Medical Subject Headings], 3. Good health, Cell biology, Intercellular Signaling Peptides and Proteins, Diseases::Immune System Diseases::Immunologic Deficiency Syndromes::HIV Infections [Medical Subject Headings], Stem cell, Naive T cell, Science, T cells, Context (language use), chemical and pharmacologic phenomena, Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Genetic Techniques::Gene Expression Profiling [Medical Subject Headings], Thymus Gland, Biology, General Biochemistry, Genetics and Molecular Biology, Article, 03 medical and health sciences, Immune system, Chemicals and Drugs::Amino Acids, Peptides, and Proteins::Proteins::Transcription Factors::beta Catenin [Medical Subject Headings], Antigen, Antigens, CD, Phenomena and Processes::Physiological Phenomena::Physiological Processes::Growth and Development::Aging [Medical Subject Headings], Anatomy::Tissues::Lymphoid Tissue::Thymus Gland [Medical Subject Headings], Cateninas, Animals, Humans, Anatomy::Hemic and Immune Systems::Immune System::Leukocytes::Leukocytes, Mononuclear::Lymphocytes::T-Lymphocytes::CD4-Positive T-Lymphocytes [Medical Subject Headings], Chemicals and Drugs::Biological Factors::Antigens [Medical Subject Headings], Anatomy::Cells::Stem Cells::Hematopoietic Stem Cells::Lymphoid Progenitor Cells::Precursor Cells, T-Lymphoid [Medical Subject Headings], Vía de señalización wnt, Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Rodentia::Muridae::Murinae::Mice [Medical Subject Headings], Precursor Cells, T-Lymphoid, Células T de memoria, Gene Expression Profiling, General Chemistry, biochemical phenomena, metabolism, and nutrition, 030104 developmental biology, Sistema inmunológico, Phenomena and Processes::Immune System Phenomena::Immunity::Adaptive Immunity::Immunologic Memory [Medical Subject Headings], bacteria, lcsh:Q, Citometría de flujo, Immunologic Memory, 030215 immunology
Abstract

The diversity of the naïve T cell repertoire drives the replenishment potential and capacity of memory T cells to respond to immune challenges. Attrition of the immune system is associated with an increased prevalence of pathologies in aged individuals, but whether stem cell memory T lymphocytes (TSCM) contribute to such attrition is still unclear. Using single cells RNA sequencing and high-dimensional flow cytometry, we demonstrate that TSCM heterogeneity results from differential engagement of Wnt signaling. In humans, aging is associated with the coupled loss of Wnt/β-catenin signature in CD4 TSCM and systemic increase in the levels of Dickkopf-related protein 1, a natural inhibitor of the Wnt/β-catenin pathway. Functional assays support recent thymic emigrants as the precursors of CD4 TSCM. Our data thus hint that reversing TSCM defects by metabolic targeting of the Wnt/β-catenin pathway may be a viable approach to restore and preserve immune homeostasis in the context of immunological history., Aging is associated with immune attrition that may impact the effectiveness of the immune system to protect the host from pathogens. Here the authors show that immune aging is associated with alterations in the Wnt/β-catenin signaling and reduced stem cell memory T lymphocytes, hinting the Wnt/β-catenin pathway as a potential therapy target.

Published
2020

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