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Analyse et exploitation de signatures transcriptomiques de patients infectés par des virus respiratoires en vue du repositionnement de médicaments pour de nouvelles indications thérapeutiques antivirales

Abstract : Acute respiratory infections (ARIs) are caused by many pathogens and among them, respiratory viruses hold a very privileged place. Epidemiological studies have highlighted numerous cases of infections caused by rhinoviruses, adenoviruses, pneumoviruses (Respiratory Syncytial Virus and Human Metapneumovirus) or even coronaviruses, but also influenza and parainfluenza viruses. Young children and immunocompromised or elderly people are considered at risk populations, but no age group is spared from these viral respiratory infections. These remain a major cause of consultations, hospitalizations and deaths in both developing and industrialized countries. They are the leading cause of death in young children (more than 2 million deaths per year) and their annual direct cost to our societies is estimated at 2.5 billion euros. Despite this, the therapeutic and / or prophylactic arsenal is very scarce except for influenza viruses, but remains nevertheless limited. The emergence of influenza strains resistant to the few antivirals on the market is indeed a source of major concern, as is the protection conferred by annual vaccines which is sometimes suboptimal, due to the variability of seasonal viral strains. In this context of unmet medical needs and major health and economic issues, my thesis work was part of a research program (RESPIROMIX) which proposes an innovative strategy for the development of antivirals, based on the repositioning of drugs already on the market for new anti- infectious therapeutic indications. My work focused on the characterization and exploitation of transcriptomic signatures of in vivo (bank of biological samples from infected patients) and in vitro (model of human respiratory epithelium cultivated at the air / liquid interface) infections, obtained by hybridization on Affymetrix chips and by high throughput sequencing (NGS), respectively. Our informed choice of tools and the implementation of an adapted and optimized pipeline enabled the differential and functional analyses of these virogenomic signatures, as well as their comparison with a set of chemogenomic signatures, from the Connectivity Map database (CMap). This database is a collection of expression data from human cells in culture treated or not with small bioactive molecules (more than 7 000 gene expression profiles corresponding to 1 309 compounds). My results have notably contributed to (i) the identification and repositioning of Diltiazem, a drug usually used as an antihypertensive, as an inhibitor of influenza viruses, and (ii) the characterization in experimental in vitro and murine models of diltiazem mode of action (MoA), which leads to the endogenous activation of type III interferon genes and metabolic biosynthesis pathways. These results enabled the setup of a multicentric phase II clinical trial (FLUNEXT TRIAL PHRC n°15-0442) aiming to evaluate the use of Diltiazem in the management of patients admitted to intensive care for severe influenza. In the same dynamic, the methodology and pipeline developed during my doctoral work have also led, based on signatures of infected patients, to the selection of several drugs for their therapeutic repositioning against pneumovirus infections (HRSV and HMPV). Some of these candidates are currently being validated in our in vitro and murine models of infections
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Submitted on : Thursday, July 29, 2021 - 3:51:11 PM
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Claire Nicolas de Lamballerie. Analyse et exploitation de signatures transcriptomiques de patients infectés par des virus respiratoires en vue du repositionnement de médicaments pour de nouvelles indications thérapeutiques antivirales. Bio-informatique [q-bio.QM]. Université de Lyon, 2020. Français. ⟨NNT : 2020LYSE1118⟩. ⟨tel-03307577⟩

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