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Septembre 2022



Amphi Pasteur

Séminaire Externe

 « Host-directed drug-screening uncovers new SARS-CoV-2 entry factors »

Dr Vincent GRASS ( Technical University of Munich, School of Medicine, Institute of Virology, Munich, Germany)
Contact : Marlène Dreux
COVID-19 is a complex disease characterized by fulminant replication of SARS-CoV-2 and associated virusinduced comorbidities. Here, we performed genome-scale analyses combining interactome studies of SARS-CoV-2 along with transcriptome, proteome, ubiquitinome and phosphoproteome of infected cells, and as compared to SARS-CoV-1. Next, our multiple datasets were projected onto the global network of cellular interactions, enabling the identification of distinct and common hotspots that could be targeted by repurposed antiviral therapies. Notably, we further performed high-throughput inhibitor screens leading to identify host metalloproteases as newly-assigned proviral factors. Moreover, a CRISPR-based knock-out screen led to the characterization of ADAM17 as a facilitator of SARS-CoV-2 cell entry and ADAM10 as a host factor required for lung cell syncytia formation, a hallmark of COVID-19 pathology. Similar workflow was then used to i) repurpose antiviral drugs against both viral and host enzymes, thus to pharmaceutically block methylation of the viral RNA 2'-O-ribose cap, and ii) characterize unconventional host factors regulating endosomal maturation and SARS coronavirus entry.
Overall, combing genome-wide approaches with screening for drug repurposing led to the identification for new key host factors, and hereby novel antiviral compounds which exerted strong ex vivo activity at the nanomolar range.

Lundi 12/09/2022


Séminaire Externe

 « Single cell analysis to elucidate mechanisms underlying oncogenesis caused by HTLV-1 »

Pr. Yorifumi SATOU (Research Center for Human Retrovirus Infection, Kumamoto and Kagoshima Universities. – Japon)
Contact : Hélène Dutartre & Jocelyn Turpin
Human T-cell leukemia virus type 1 (HTLV-1) mainly infect CD4+ T-cells and induces chronic, persistent infection in infected individuals with some progressing to develop adult T-cell leukemia/lymphoma (ATL). HTLV-1 alters cellular differentiation, activation and survival but it is unknown if this contributes to malignant transformation. In this study, we used single-cell RNA-sequencing and TCR-sequencing to investigate T-cell differentiation and HTLV-1-mediated transformation processes. We analyzed 87,742 single cells from peripheral blood of 12 infected and 3 uninfected individuals. Trajectory analysis successfully captured physiological T-cell activation dynamics as well as ATL progression as a continuous process. Naive T-cells dynamically change into activated T-cells including infected cells, which seamlessly transitioned into ATL cells characterized by clonally expanded, highly-activated T-cells. In conclusion, our study revealed the mechanisms of HTLV-1-mediated transformation in vivo at single-cell level.

Mercredi 14/09/2022

Amphi Pasteur

Séminaire Externe

 « Neuronal Control of Cutaneous Inflammation »

Pr. Daniel KAPLAN (University of Pittsburgh - Pittsburgh – USA)
Contact: Marc Vocanson
Sensory neurons in the skin have recently been shown to play important roles in the development of cutaneous inflammation. In this seminar, Dr. Kaplan will review current work in his laboratory demonstrating that pain-sensing neurons are sufficient to trigger Type-17 inflammation and defining the molecular pathways involved. In addition, work defining how different sensory neurons suppress inflammation by reprogramming mast cells to become hyporesponsive will be discussed.

Mardi 22/09/2022


Amphi Pasteur

Séminaire Externe

 « Role of soluble CD95L in the pathology progression of auto-immune disorders such as lupus and ANCA vasculitis »

Dr. Patrick LEGEMBRE (Faculté de Pharmacie, U1262 INSERM, Limoges – France)
Contact: Thierry Defrance
CD95L (also known as FasL or CD178) belongs to the Tumor necrosis factor (TNF) superfamily. This transmembrane ligand can be cleaved by metalloproteases to release a soluble CD95L designated s-CD95L. While the interaction of the membrane-bound CD95L (m-CD95L) to its receptor CD95 (Fas) induces an apoptotic signal leading to cell death, s-CD95L fails to do it and triggers non-apoptotic signaling pathways (e.g., PI3K, NFkB).
We observed that s-CD95L is increased in lupus and ANCA vasculitis patients and this cytokine promotes inflammation using different mechanisms and targeting different immune cells. From these observations, different drugs were designed to selectively prevent the non-apoptotic signal without affecting the apoptotic one, which is essential to eliminate infected and transformed cells. The pro-inflammatory mechanism induced by s-CD95L accumulation will be discuss in this presentation.

Mardi 27/09/2022


Sous-sol LR5

Séminaire externe

 « A new physiological function for an endogenous envelope glycoprotein »

Jean-Luc BATTINI (IRIM Montpellier)
Contact: François-Loïc Cosset
Hundreds of endogenous retroviruses (ERV) are contained in vertebrate genomes as inactive elements and very few of them have retained intact envelope glycoproteins (Env) during evolution. No physiological role for these Envs is known, with the exception of the human ERV-W (HERV-W) env which encodes the well-known syncytins required for syncytiotrophoblast membrane fusion during placentation. I will present work from our lab highlighting a new physiological role in cellular metabolism and cell survival of a truncated endogenous Env previously identified as a restriction factor against retroviral infections.

Jeudi 29/09/2022


Amphi Pasteur

Séminaire externe

 « Antiviral activities of anti-HIV-1 and anti-SARS-CoV-2 antibodies »

Dr. Timothée BRUEL (Institut Pasteur - Unité Virus et Immunité)
Contact: Mathieu Mateo
Antibodies are produced by B cells as part of immune responses. They are polyfunctional molecules, recognizing foreign molecular motifs through their variable domains and interacting with immune cells via their constant region (Fc region). Our goal is to unravel the landscape of antiviral activities of antibodies and underlying mechanisms in the context of HIV-1 and SARS-CoV-2 infections.
Recombinant broadly neutralizing antibodies (bNAbs) targeting the HIV-1 envelope glycoprotein (Env) are promising molecules for therapeutic or prophylactic interventions. We have characterized their capacity to eliminate infected cells by NK-mediated antibody dependent cellular cytotoxicty (ADCC) and complement activation. We have also identified an additional antiviral activity of bNAbs, which block HIV-1 release by tethering viral particles at the surface of infected cells. In the context of SARS-CoV-2, we have developed a pipeline to isolate circulating viral strains and investigate their profile of neutralization by sera from convalescent and vaccinated individuals, as well as therapeutic antibodies. We also set-up assays to quantify ADCC of SARS-CoV-2 infected cells and used them to investigate the immune responses of asymptomatic individuals.
Overall, our projects aim at providing a basic understanding of antibody polyfunctionality and viral countermeasures, with implications for the development of the next generations of antibody-based vaccines and therapies.













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