PhD defense of Layla EL KAMALI on December 11th 2024

Layla EL KAMALI will defend her PhD thesis on December 11, 2024, at 14:00 p.m. (Reunion time), in the ELIE amphitheater at the University of Reunion Island, Moufia, Saint-Denis.

Elucidating intestinal antiviral responses against SARS-CoV-2 using Drosophila melanogaster as a model organism 

Abstract: The emergence of SARS-CoV-2 in December 2019 sparked a global pandemic, resulting in over 7 million deaths and profound socio-economic disruptions. While SARS-CoV-2 primarily targets the respiratory tract, extrapulmonary effects particularly gastrointestinal (GI) symptoms, are widely reported, affecting up to 60% of COVID-19 patients. The underlying mechanisms for these effects appear multifactorial and remain poorly understood, necessitating the use of animal models to dissect these complex processes. To study SARS-CoV-2-induced intestinal pathology, we used Drosophila melanogaster as a model due to structural and molecular parallelisms between the Drosophila and mammalian guts. Additionally, the fly gut exhibits high expression of Ance, an orthologue of the angiotensin-converting enzyme 2 (ACE2), the key receptor for viral entry. Our findings demonstrate that Drosophila is permissive to oral SARS-CoV-2 infection, confirmed by RT-qPCR, PFU assays, and immunofluorescence, with susceptibility evidenced by reduced survival rates. Interestingly, viral infection induces structural disruptions in the intestine, characterized by reduced gut size, contraction of visceral muscles, and other physiological impairments. Using genetic tools and specific cell markers, we showed that SARS-CoV-2 alters the cellular composition of the intestinal epithelium. Specifically, infection leads to enterocyte death (digestive and absorptive cells), a reduction in enteroendocrine cells (hormone-secreting cells), and a sustained increased number of intestinal stem cells (ISCs) and their progenitors, alongside a block in their differentiation. Transcriptomic analysis reveals a biphasic intestinal response to infection: an initial activation phase marked by disturbed metabolic pathways, particularly lipid metabolism, followed by a repressive phase affecting mainly cellular differentiation. Further analysis reveals a compartmentalized disruption of lipid homeostasis, with lipid droplets accumulating in the posterior gut and depleting in anterior segments, suggesting a viral strategy that regionally exploits host lipid reserves to facilitate replication. Finally, we evaluated the efficacy of plitidepsin, an antiviral currently in Phase II/III clinical trials, in modulating intestinal SARS-CoV-2 infection in Drosophila. Oral administration of plitidepsin significantly mitigated pathological effects, preserving intestinal epithelial integrity and stabilizing lipid homeostasis. This thesis establishes the Drosophila midgut as a powerful model for dissecting SARS-CoV-2-induced GI pathogenesis, offering promising avenues for identifying novel therapeutic strategies. By examining SARS-CoV-2’s impact on intestinal architecture, stem cell lineage dynamics, and lipid metabolism, our model provides a robust platform to decipher gastrointestinal infections related to COVID-19 and guide the development of targeted treatments.

Keywords : SARS-CoV-2, infectious diseases, Drosophila melanogaster, intestinal infection, lipid metabolism, plitidepsin, antiviral.

Members of the jury
Pr. Leen Delang.   KU Leuven.   Reviewer.
Dr. Nuria Romero. University of Côte d’Azur.  Reviewer.
Pr. Bassam Badran. Lebanese University. Examiner
Dr. Karin Seron. Pasteur Institute of Lille. Examiner
Dr. Pauline Speder. University Paris-Cité. Examiner