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1. Cytotoxicity of human antibodies targeting the circumsporozoite protein is amplified by 3D substrate and correlates with protection

Author

Aguirre-Botero, Manuela, Wang, Lawrence, Formaglio, Pauline, Aliprandini, Eduardo, Thiberge, Jean-Michel, Schön, Arne, Flores-Garcia, Yevel, Mathis-Torres, Shamika, Flynn, Barbara, da Silva Pereira, Lais, Le Duff, Yann, Hurley, Mathew, Nacer, Adéla, Bowyer, Paul, Zavala, Fidel, Idris, Azza, Francica, Joseph, Seder, Robert, Amino, Rogerio, Infection et Immunité paludéennes - Malaria Infection and Immunity, Institut Pasteur [Paris] (IP)-Université Paris Cité (UPCité), École Doctorale Bio Sorbonne Paris Cité [Paris] (ED562 - BioSPC), Université Sorbonne Paris Cité (USPC)-Université Paris Cité (UPCité), National Institutes of Health [Bethesda] (NIH), Johns Hopkins University (JHU), Johns Hopkins Malaria Research Institute [Baltimore], Johns Hopkins Bloomberg School of Public Health [Baltimore], Johns Hopkins University (JHU)-Johns Hopkins University (JHU), National Institute for Biological Standards and Control (NIBSC), Medicines and Healthcare Products Regulatory Agency (MHRA), This work was supported by funds from the Institut Pasteur, the Agence Nationale de la Recherche (ANR, French National Research Agency)/Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) – project number SporoSTOP ANR-19-CE15-0027, and the French Government’s Investissement d’Avenir program, Laboratoire d’Excellence 'Integrative Biology of Emerging Infectious Diseases' – project number ANR-10-LABX-62-IBEID. M.C.A.-B. is funded by the Pasteur - Paris University International PhD Program. A.S. was supported by contract HHSN261200800001E from the National Cancer Institute, NIH. Y.F.-G. and F.Z. thank the Bill and Melinda Gates Foundation and Bloomberg Philanthropies for their continued support. The antibodies provided by the Center for AIDS Reagents repository at the National Institute for Biological Standards and Control, UK (6F8 and 2C4) were produced through the European Commission FP7 European Research Infrastructures for Poverty Related Diseases (EURIPRED) project (INFRA-2012-312661), funded by the European Union’s Seventh Framework Programme (FP7/2007–2013) under grant agreement no. 312661 – EURIPRED. The graphical abstract was created with BioRender.com, We would like to thank the team of the Center for Production and Infection of Anopheles (CEPIA, C2RA, Institut Pasteur) for providing mosquitoes, the staff of Central Animal Facility (C2RA, Institut Pasteur) for animal care, and the team of the Photonic BioImaging platform (UTechS PBI, C2RT, Institut Pasteur) for providing access to the spinning-disk microscope and support., ANR-19-CE15-0027,SporoSTOP,Neutralisation des sporozoïtes de Plasmodium dans la peau de l'hôte(2019), ANR-10-LABX-0062,IBEID,Integrative Biology of Emerging Infectious Diseases(2010), and European Project: 312661,EC:FP7:INFRA,FP7-INFRASTRUCTURES-2012-1,EURIPRED(2013)

Subjects
[SDV]Life Sciences [q-bio], [SDV.IMM]Life Sciences [q-bio]/Immunology, [SDV.MP.PAR]Life Sciences [q-bio]/Microbiology and Parasitology/Parasitology
Abstract

International audience; Human monoclonal antibodies (hmAbs) targeting the Plasmodium falciparum circumsporozoite protein (PfCSP) on the sporozoite surface are a promising tool for preventing malaria infection. However, their mechanisms of protection remain unclear. Here, using 13 distinctive PfCSP hmAbs, we provide a comprehensive view of how PfCSP hmAbs neutralize sporozoites in host tissues. Sporozoites are most vulnerable to hmAb-mediated neutralization in the skin. However, rare but potent hmAbs additionally neutralize sporozoites in the blood and liver. Efficient protection in tissues mainly associates with high-affinity and high-cytotoxicity hmAbs inducing rapid parasite loss-of-fitness in the absence of complement and host cells in vitro. A 3D-substrate assay greatly enhances hmAb cytotoxicity and mimics the skin-dependent protection, indicating that the physical stress imposed on motile sporozoites by the skin is crucial for unfolding the protective potential of hmAbs. This functional 3D cytotoxicity assay can thus be useful for downselecting potent anti-PfCSP hmAbs and vaccines.

Published
2023

2. CRISPR/Cas9 -mediated gene knockout of Anopheles gambiae FREP1 suppresses malaria parasite infection

Author

George Dimopoulos, Yuemei Dong, Eric Marois, Maria L. Simões, W. Harry Feinstone Department of Molecular Microbiology and Immunology [Baltimore, MD, États-Unis] (MMI), Johns Hopkins Bloomberg School of Public Health [Baltimore], Johns Hopkins University (JHU)-Johns Hopkins University (JHU), Modèles Insectes de l'Immunité Innée (M3I), Institut de biologie moléculaire et cellulaire (IBMC), Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), This work was supported by the National Institutes of Health / National Institute of Allergy and Infectious Disease grants R21AI131574 (to GD) and RO1AI122743 (to GD), and a Johns Hopkins Malaria Research Institute Postdoctoral Fellowship (to MLS), the Bloomberg Philanthropies (to GD). CNRS, Inserm, the University of Strasbourg and Agence Nationale de la Recherche (grants JCJC 'GEMM' and #ANR-11-EQPX-0022) to EM., ANR-11-JSV3-0001,GEMM,Outils génétiques pour la manipulation du génome d'Anopheles gambiae(2011), ANR-11-EQPX-0022,I2MC,Insectarium pour l'Infectiologie Moléculaire et Cellulaire(2011), Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de biologie moléculaire et cellulaire (IBMC), Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS), Bodescot, Myriam, Jeunes Chercheuses et Jeunes Chercheurs - Outils génétiques pour la manipulation du génome d'Anopheles gambiae - - GEMM2011 - ANR-11-JSV3-0001 - JCJC - VALID, and Equipements d'excellence - Insectarium pour l'Infectiologie Moléculaire et Cellulaire - - I2MC2011 - ANR-11-EQPX-0022 - EQPX - VALID

Subjects
0301 basic medicine, Plasmodium, Physiology, Anopheles gambiae, Disease Vectors, Mosquitoes, Synthetic Genome Editing, Genome Engineering, Gene Knockout Techniques, Mice, 0302 clinical medicine, Medicine and Health Sciences, CRISPR, Malaria, Falciparum, lcsh:QH301-705.5, Protozoans, Anopheles, Malarial Parasites, Crispr, Eukaryota, 3. Good health, Body Fluids, Insects, Infectious Diseases, Blood, [SDV.MP]Life Sciences [q-bio]/Microbiology and Parasitology, Sporozoites, Engineering and Technology, Insect Proteins, Synthetic Biology, Anatomy, Research Article, Biotechnology, lcsh:Immunologic diseases. Allergy, Arthropoda, Immunology, Plasmodium falciparum, Bioengineering, Biology, Research and Analysis Methods, Microbiology, Gene Knockout, 03 medical and health sciences, Virology, Parasite Groups, parasitic diseases, Genetics, medicine, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, Parasitic Diseases, Animals, Humans, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Molecular Biology Techniques, [SDV.MP] Life Sciences [q-bio]/Microbiology and Parasitology, Molecular Biology, Gene knockout, Cas9, Organisms, Oocysts, Biology and Life Sciences, Synthetic Genomics, biology.organism_classification, medicine.disease, Tropical Diseases, Invertebrates, Parasitic Protozoans, Insect Vectors, Malaria, Species Interactions, 030104 developmental biology, lcsh:Biology (General), Synthetic Bioengineering, Artificial Genetic Recombination, Parasitology, CRISPR-Cas Systems, lcsh:RC581-607, Apicomplexa, 030217 neurology & neurosurgery
Abstract

Plasmodium relies on numerous agonists during its journey through the mosquito vector, and these agonists represent potent targets for transmission-blocking by either inhibiting or interfering with them pre- or post-transcriptionally. The recently developed CRISPR/Cas9-based genome editing tools for Anopheles mosquitoes provide new and promising opportunities for the study of agonist function and for developing malaria control strategies through gene deletion to achieve complete agonist inactivation. Here we have established a modified CRISPR/Cas9 gene editing procedure for the malaria vector Anopheles gambiae, and studied the effect of inactivating the fibrinogen-related protein 1 (FREP1) gene on the mosquito’s susceptibility to Plasmodium and on mosquito fitness. FREP1 knockout mutants developed into adult mosquitoes that showed profound suppression of infection with both human and rodent malaria parasites at the oocyst and sporozoite stages. FREP1 inactivation, however, resulted in fitness costs including a significantly lower blood-feeding propensity, fecundity and egg hatching rate, a retarded pupation time, and reduced longevity after a blood meal., Author summary The causative agent of malaria, Plasmodium, has to complete a complex infection cycle in the Anopheles gambiae mosquito vector in order to reach the salivary gland from where it can be transmitted to a human host. The parasite’s development in the mosquito relies on numerous host factors (agonists), and their inhibition or inactivation can thereby result in suppression of infection and consequently malaria transmission. The recently developed CRISPR/Cas9-based genome editing tools for Anopheles mosquitoes provide new and promising opportunities to delete (inactivate) Plasmodium agonists to better understand their function and for blocking malaria transmission. Here we have established a modified CRISPR/Cas9 genome editing technique for malaria vector A. gambiae mosquitoes. Through this approach we have inactivated the fibrinogen-related protein 1 (FREP1) gene, via CRISPR/Cas9 genome editing, and the impact of this manipulation on the mosquito’s susceptibility to Plasmodium and on mosquito fitness. FREP1 knockout mutants showed a profound suppression of infection with both human and rodent malaria parasites, while it also resulted in fitness costs: a significantly lower blood-feeding propensity, fecundity and egg hatching rate, and a retarded larval development and pupation time, and reduced longevity after a blood meal.

Published
2018

3. In vivo imaging of CD8 + T cell-mediated elimination of malaria liver stages

Author

Vitaly V. Ganusov, Andrea J. Radtke, Reka K. Kelemen, Fidel Zavala, Rogerio Amino, Sze Wah Tse, Scot C. Kuo, Ian A. Cockburn, Robert Ménard, Laura Mac-Daniel, Johns Hopkins Malaria Research Institute [Baltimore], Johns Hopkins Bloomberg School of Public Health [Baltimore], Johns Hopkins University (JHU)-Johns Hopkins University (JHU), W. Harry Feinstone Department of Molecular Microbiology and Immunology [Baltimore, MD, États-Unis] (MMI), Biologie et Génétique du Paludisme, Institut Pasteur [Paris], Genome Science and Technology, The University of Tennessee [Knoxville], Johns Hopkins University School of Medicine [Baltimore], R.M. is supported by Grant ANR-10-LABX-62-IBEID from the French Government’s Investissement d’Avenir program, and R.A. by the French National Research Agency Grant ANR-10-JCJC-1302-PlasmoPEP. Work in the F.Z. laboratory was supported by National Institutes of Health Grant AI44375 (to F.Z.) and an European Molecular Biology Organization short-term fellowship (to I.A.C.). F.Z. and I.A.C. receive support from the Bloomberg Family Foundation., We thank Dr. Yun-Chi Chen for providing recombinant vaccinia virus, Dr. Pascale Gueirard for animal breeding, Center for Production and Infection of Anopheles for providing mosquitoes, and IMAGOPOLE for the imaging platform., ANR-10-LABX-0062,IBEID,Integrative Biology of Emerging Infectious Diseases(2010), ANR-10-JCJC-1302,PlasmoPEP,Imagerie in vivo de la phase pre-erythrocitaire du paludisme(2010), and Institut Pasteur [Paris] (IP)

Subjects
lymphocytes, Plasmodium, Epitopes, T-Lymphocyte, CD8-Positive T-Lymphocytes, MESH: CD8-Positive T-Lymphocytes/immunology, Parasite Load, Mice, Interleukin 21, 0302 clinical medicine, MESH: Reverse Transcriptase Polymerase Chain Reaction, MESH: Receptors, Antigen, T-Cell/metabolism, Cytotoxic T cell, MESH: Animals, IL-2 receptor, Mice, Inbred BALB C, 0303 health sciences, Microscopy, Confocal, Multidisciplinary, Reverse Transcriptase Polymerase Chain Reaction, MESH: Malaria/parasitology, CD28, Biological Sciences, Natural killer T cell, Adoptive Transfer, MESH: Microscopy, Confocal/methods, MESH: Liver/parasitology, 3. Good health, Cell biology, MESH: CD8-Positive T-Lymphocytes/ultrastructure, Liver, [SDV.IMM.IA]Life Sciences [q-bio]/Immunology/Adaptive immunology, MESH: Malaria/immunology, MESH: Epitopes, T-Lymphocyte/metabolism, MESH: Mice, Transgenic, MESH: Models, Immunological, Green Fluorescent Proteins, Antigen presentation, Receptors, Antigen, T-Cell, MESH: Mice, Inbred BALB C, Mice, Transgenic, MESH: Green Fluorescent Proteins/metabolism, Streptamer, Biology, Time-Lapse Imaging, Cell Line, MESH: Plasmodium/immunology, 03 medical and health sciences, Animals, Antigen-presenting cell, MESH: Mice, 030304 developmental biology, MESH: Liver/immunology, Models, Immunological, MESH: Time-Lapse Imaging/methods, immunity, Malaria, MESH: Cell Line, MESH: Parasite Load, MESH: Adoptive Transfer, 030215 immunology
Abstract

CD8 + T cells are specialized cells of the adaptive immune system capable of finding and eliminating pathogen-infected cells. To date it has not been possible to observe the destruction of any pathogen by CD8 + T cells in vivo. Here we demonstrate a technique for imaging the killing of liver-stage malaria parasites by CD8 + T cells bearing a transgenic T cell receptor specific for a parasite epitope. We report several features that have not been described by in vitro analysis of the process, chiefly the formation of large clusters of effector CD8 + T cells around infected hepatocytes. The formation of clusters requires antigen-specific CD8 + T cells and signaling by G protein-coupled receptors, although CD8 + T cells of unrelated specificity are also recruited to clusters. By combining mathematical modeling and data analysis, we suggest that formation of clusters is mainly driven by enhanced recruitment of T cells into larger clusters. We further show various death phenotypes of the parasite, which typically follow prolonged interactions between infected hepatocytes and CD8 + T cells. These findings stress the need for intravital imaging for dissecting the fine mechanisms of pathogen recognition and killing by CD8 + T cells.

Published
2013

4. Mosquito Feeding Assays to Determine the Infectiousness of Naturally Infected Plasmodium falciparum Gametocyte Carriers

Author

Yimin Wu, Ashley J. Birkett, Patricia M. Graves, Mouctar Diallo, Louis Clément Gouagna, Thomas S. Churcher, Merribeth J. Morin, Mamadou B. Coulibaly, Bert Mulder, Teun Bousema, Robert W. Sauerwein, Chris Drakeley, Ogobara K. Doumbo, Will Roeffen, Rhoel R. Dinglasan, Isabelle Morlais, Vincent Robert, Yeya T. Touré, G. A. T. Targett, Parfait Awono-Ambene, Emily Locke, Timoléon Tchuinkam, Sarah Bonnet, Colin J. Sutherland, Travis van Warmerdam, London School of Hygiene and Tropical Medicine (LSHTM), Radboud university [Nijmegen], Johns Hopkins Bloomberg School of Public Health [Baltimore], Johns Hopkins University (JHU), Institut de Recherche Agricole pour le Développement [Yaoundé] (IRAD), Institut de Recherche pour le Développement, Partenaires INRAE, Institut de Recherche pour le Développement (IRD), Malaria Res Inst, Biologie Moléculaire et Immunologie Parasitaires et Fongiques, École nationale vétérinaire d'Alfort (ENVA)-Institut National de la Recherche Agronomique (INRA)-Agence nationale de sécurité sanitaire de l'alimentation, de l'environnement et du travail (ANSES)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Université des sciences, des techniques et des technologies de Bamako (USTTB), Laboratorium Microbiologie Twente, James Cook University (JCU), PATH Malaria Vaccine Initiat, NIAID, Imperial College London, Bill & Melinda Gates Foundation, European FP7 framework (REDMAL) [242079], PATH Malaria Vaccine Initiative (MVI), MVI, Bloomberg Family Foundation, Johns Hopkins Malaria Research Institute, Institut de Recherche pour le Developpement, TMRC, NIAID/NIH, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, EC FP7 Collaborative project TransMalariaBloc [HEALTH-F3-2008-223736], Radboud University [Nijmegen], École nationale vétérinaire - Alfort (ENVA)-Institut National de la Recherche Agronomique (INRA)-Agence nationale de sécurité sanitaire de l'alimentation, de l'environnement et du travail (ANSES)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), and Université des Sciences, des Techniques et des Technologies de Bamako (USTTB)

Subjects
Male, moustique, Epidemiology, [SDV]Life Sciences [q-bio], lcsh:Medicine, test cutané, Skin infection, Plasmodium, 0302 clinical medicine, Poverty-related infectious diseases Infection and autoimmunity [N4i 3], Blood plasma, Malaria, Falciparum, lcsh:Science, Child, Whole blood, 0303 health sciences, Multidisciplinary, biology, Transmission (medicine), Anopheles, Middle Aged, maladie parasitaire, 3. Good health, skin infections, Infectious Diseases, Child, Preschool, Medicine, Female, Research Article, Adult, Adolescent, Plasmodium falciparum, 030231 tropical medicine, malaria, gametocyte, Microbiology, Infectious Disease Epidemiology, Young Adult, 03 medical and health sciences, parasitic diseases, Parasitic Diseases, medicine, Gametocyte, sang, Animals, Humans, Biology, 030304 developmental biology, Population Biology, lcsh:R, Infant, plasma sanguin, medicine.disease, biology.organism_classification, Virology, infection, Insect Vectors, paludisme, Immunology, lcsh:Q, Parasitology, Malaria
Abstract

Contains fulltext : 108727.pdf (Publisher’s version ) (Open Access) INTRODUCTION: In the era of malaria elimination and eradication, drug-based and vaccine-based approaches to reduce malaria transmission are receiving greater attention. Such interventions require assays that reliably measure the transmission of Plasmodium from humans to Anopheles mosquitoes. METHODS: WE COMPARED TWO COMMONLY USED MOSQUITO FEEDING ASSAY PROCEDURES: direct skin feeding assays and membrane feeding assays. Three conditions under which membrane feeding assays are performed were examined: assays with i) whole blood, ii) blood pellets resuspended with autologous plasma of the gametocyte carrier, and iii) blood pellets resuspended with heterologous control serum. RESULTS: 930 transmission experiments from Cameroon, The Gambia, Mali and Senegal were included in the analyses. Direct skin feeding assays resulted in higher mosquito infection rates compared to membrane feeding assays (odds ratio 2.39, 95% confidence interval 1.94-2.95) with evident heterogeneity between studies. Mosquito infection rates in membrane feeding assays and direct skin feeding assays were strongly correlated (p

Published
2012

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