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Dengue Virus Diverts the Mosquito Phospholipid Metabolism for Replication Thomas Vial

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Dengue Virus Diverts the Mosquito Phospholipid Metabolism for Replication Thomas Vial Dengue virus diverts the mosquito phospholipid metabolism for replication Thomas Vial To cite this version: Thomas Vial. Dengue virus diverts the mosquito phospholipid metabolism for replication. Virology. Université Paul Sabatier - Toulouse III, 2020. English. NNT : 2020TOU30036. tel-02980597 HAL Id: tel-02980597 https://tel.archives-ouvertes.fr/tel-02980597 Submitted on 27 Oct 2020 HAL is a multi-disciplinary open access L’archive ouverte pluridisciplinaire HAL, est archive for the deposit and dissemination of sci- destinée au dépôt et à la diffusion de documents entific research documents, whether they are pub- scientifiques de niveau recherche, publiés ou non, lished or not. The documents may come from émanant des établissements d’enseignement et de teaching and research institutions in France or recherche français ou étrangers, des laboratoires abroad, or from public or private research centers. publics ou privés. THÈSE En vue de l’obtention du DOCTORAT DE L’UNIVERSITÉ DE TOULOUSE Délivré par l'Université Toulouse 3 - Paul Sabatier Présentée et soutenue par Thomas VIAL Le 29 Juin 2020 Le virus de la dengue détourne le métabolisme des phospholipides du moustique pour sa réplication Ecole doctorale : BSB - Biologie, Santé, Biotechnologies Spécialité : MICROBIOLOGIE Unité de recherche : PHARMA-DEV -Laboratoire Pharmacochimie et Pharmacologie pour le Développement Thèse dirigée par Eric DEHARO Jury M. Louis Lambrechts, Rapporteur M. Jean-Luc Imler, Rapporteur Mme Isabelle Morlais, Examinatrice M. Jean-Charles Portais, Examinateur M. Eric Deharo, Directeur de thèse M. Julien Pompon, Co-directeur de thèse M. Guillaume Marti, Invité Dengue virus diverts the mosquito phospholipid metabolism for effective infection Thomas Vial École Doctorale BSB – Biologie, Santé, Biotechnologies Université Toulouse 3 - Paul Sabatier 2 ACKNOWLEDGMENTS These four years spent on this project have been intense, first by being based in Laos and travelling to Singapore and Toulouse to initiate the project, and then full time in Singapore. I would like to thank here all the people who contributed in any way to the realization of this thesis work in the best conditions. First of all, I would like to thank Eric Deharo, my thesis director, who allowed me to be part of this incredible experience in Laos four years ago, by opening the doors of the IRD to me and get back to research work. Thank you for your confidence on all these different projects and especially for proposing me this research project by sending me to Singapore. You pushed me to enroll a thesis, which was not necessarily in my plans at the beginning. I would also like to thank the person who supported and accompanied me tirelessly throughout this research project, my thesis co-director Julien Pompon. Thank you welcoming me at Duke- NUS and for allowing me to turn those valuable preliminary data into a thesis project. I do not count the precious advices, rereading, Skype meeting to lead to the big picture and to get the right message. Your availability and your support on the analysis and writing of the papers and the manuscript were essential. I particularly thank Mariano Garcia-Blanco for having done me the honor of joining his laboratory and for having taken advantage of his always brilliant remarks and advice. Thanks also to Linfa Wang for his welcome to the EID department. Of course, I warmly thank the members of the MGB lab team. Thanks to Shi-Chia, Mayra and KC for bringing me their experience and advices. Thanks to Vanessa and Ben for their technical support and especially to Wei Lian for helping me a lot, especially at the end of the thesis for many experiments. Thanks to Menchie for training me in insectary and for providing me with a lot of mosquitoes. I can't count the hours spent sorting female mosquitoes, dissecting midgut or testicles in the heat and humidity. I would like to thank Guillaume Marti for training and coaching me on the metabolomics part and for welcoming me during my stays in Toulouse. These numerous samples and long hours of mass spectrometry provided a considerable amount of data. I would like to thank Nicolas Fabre for his welcome at Pharmadev and the members of UMR-152 whom I was able to meet briefly. Thanks to Franck for helped me during my stays in the lab and for received my numerous shipments of samples from Singapore. Thanks to the members of the thesis committee, Mariano, Eng Eong Ooi and Jean-Paul Kovalic, for helping me to share my results at important moments and to oriented me on the project. Finally, I would like to thank my family and friends who gave me their support despite the distance. First of all, my parents and my sister, who encouraged me from the beginning, when I left France. My friends and the many discussions on WhatsApp that kept me connected. Finally, I would like to thank my wife, Melanie, the first to support me, without whom it would have been difficult to move forward in the same way and with whom I look forward to sharing the next adventures. 3 ABSTRACT More than half of the world population is at risk of dengue virus (DENV) infection because of the global distribution of its mosquito vectors. There is neither effective vaccine nor therapeutics. The only available strategy relies on insecticides, against which mosquitoes are developing resistance. Viruses utilize the host metabolome for replication and dissemination. This is particularly true for envelope viruses like DENV that relies on host lipid membranes to complete their life-cycle. To reach an optimal metabolic environment, viruses subvert the host metabolome. Understanding DENV-mosquito metabolic interactions will reveal novel strategies to stop DENV transmission. Here, we characterized how DENV hijacks the Aedes aegypti mosquito lipidome to identify targets for novel transmission-blocking interventions. To describe metabolic changes throughout the mosquito DENV cycle, we deployed a Liquid chromatography–high resolution mass spectrometry (LC-HRMS) workflow at different stages of vector infection. We revealed a major phospholipid reconfiguration throughout the DENV mosquito cycle, in cells, midguts, and whole mosquitoes. To decipher how DENV reconfigures phospholipids, we phylogenetically characterized acylglycerolphosphate acyltransferase (AGPAT) enzyme isoforms and identified those (i.e., AGPAT1) that catalyze a central rate- limiting step in phospholipid biogenesis. We found that DENV infection decreased AGPAT1 expression, which depletion enhances infection by maintaining high aminophospholipid (aminoPL) concentrations, especially phosphatidylcholine (PC) and phosphatidylethanolamine (PE), during DENV mosquito cycle. By demonstrating that DENV-mediated AGPAT1 downregulation provides a proviral environment, these results reveal the first metabolic host factor in mosquitoes and emphasize the role of aminophospholipids in DENV cellular cycle. We then undertook to precise how DENV influences aminoPL biosynthesis and what stage of DENV cellular cycle requires aminoPL reconfiguration. De novo biosynthesis of PC and PE is known as the Kennedy pathway, where a diacylglycerol (DAG) incorporates either a choline or an ethanolamine group. AminoPL remodeling by deacylation/reacylation then ensures membrane dynamism that participates in membrane rearrangements. Using isotopic labelling through ethanolamine or choline supplementation, we showed that DENV modulates PC and PE biosynthesis by interacting with membrane remodeling. Further supporting the importance of the Kennedy pathway in DENV infection, ethanolamine supplementation reduced virus titer in mosquito cells by altering composition of specific PC and PE. While ethanolamine-mediated aminoPL disruption did not alter attachment, internalization or translation, it reduced replication and resulted in a lower ratio of infectious particles, likely because of deficient replication. These results strongly support the importance of aminoPLs in DENV infection of mosquitoes and reveal the importance of aminoPL composition in replication. PC and PE are the most abundant phospholipid species in eukaryotic cells and contribute to cell membrane architecture, especially in the endoplasmic reticulum, where replication takes place. Disruption of aminoPL reconfiguration may represent a novel strategy to interfere with DENV subversion of mosquito metabolome. 4 RESUME Plus de la moitié de la population mondiale est exposée au risque d'infection par le virus de la dengue (DENV) en raison de la distribution mondiale de ses moustiques vecteurs. Il n'existe ni vaccin ni traitement efficace. La seule stratégie disponible repose sur les insecticides, contre lesquels les moustiques développent une résistance. Les virus utilisent le métabolome de l'hôte pour la réplication et la dissémination. C'est particulièrement vrai pour les virus enveloppés comme le DENV qui dépend des membranes lipidiques de l'hôte pour compléter son cycle de vie. Pour atteindre un environnement métabolique optimal, les virus perturbent le métabolome de l'hôte. La compréhension de ces altérations chez les moustiques vecteurs pourrait révéler de nouvelles stratégies pour bloquer la transmission du DENV. Ici, nous avons caractérisé comment le DENV détourne le lipidome du moustique Aedes aegypti. Pour décrire les changements métaboliques tout au long du cycle du DENV chez le moustique, nous avons débeloppé une méthode de chromatographie liquide et de spectrométrie de masse à haute résolution (LC-HRMS) à différents stades de l'infection chez le vecteur. Nous avons révélé une
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