A5084861721- Influenza Virus Research Studies
- interferon and immune responses
- RNA and protein synthesis mechanisms
- RNA modifications and cancer
- Computational Drug Discovery Methods
- RNA Research and Splicing
- vaccines and immunoinformatics approaches
- SARS-CoV-2 and COVID-19 Research
- Synthesis and biological activity
- Click Chemistry and Applications
- Heat shock proteins research
- Respiratory viral infections research
- Immune Response and Inflammation
- Cancer therapeutics and mechanisms
- Virus-based gene therapy research
- Enzyme Structure and Function
Institut Pasteur
2021-2025
Department of Virology
2025
Université Paris Cité
2021-2024
Centre National de la Recherche Scientifique
2021-2024
University of Münster
2018-2023
Human infection with highly pathogenic avian influenza viruses (HPAIV) is often associated severe tissue damage due to hyperinduction of interferons and proinflammatory cytokines. The reasons for this excessive cytokine expression are still incompletely understood, which has hampered the development efficient immunomodulatory treatment options. host protein TRIM28 associates promoter regions over 13,000 genes recognized as a genomic corepressor negative immune regulator. activity regulated...
Abstract During influenza A virus (IAV) infections, viral proteins are targeted by cellular E3 ligases for modification with ubiquitin. Here, we decipher and functionally explore the ubiquitination landscape of IAV polymerase during infection human alveolar epithelial cells applying mass spectrometry analysis immuno-purified K-ε-GG (di-glycyl)-remnant-bearing peptides. We have identified 59 modified lysines across three subunits, PB2, PB1 PA which 17 distinctively affect mRNA transcription,...
Abstract The current model is that the influenza virus polymerase (FluPol) binds either to host RNA II (RNAP II) or acidic nuclear phosphoprotein 32 (ANP32), which drives its conformation and activity towards transcription replication of viral genome, respectively. Here, we provide evidence FluPol-RNAP binding interface, beyond well-acknowledged function in cap-snatching during initiation, has also a pivotal role genome. Using combination cell-based vitro approaches, show RNAP...
Replication of influenza viral RNA depends on at least two polymerases, a parental replicase and an encapsidase, cellular factor ANP32. ANP32 comprises LRR domain long C-terminal low complexity acidic region (LCAR). Here we present evidence suggesting that is recruited to the replication complex as electrostatic chaperone stabilises encapsidase moiety within apo-polymerase symmetric dimers are distinct for A B polymerases. The bound then forms asymmetric with replicase, which embedded in...
Abstract Genome-wide approaches have significantly advanced our knowledge of the repertoire RNA-binding proteins (RBPs) that associate with cellular polyadenylated mRNAs within eukaryotic cells. Recent studies focusing on RBP interactomes viral mRNAs, notably SARS-Cov-2, revealed both similarities and differences between profiles mRNAs. However, RBPome influenza virus remains unexplored. Herein, we identify RBPs mRNA encoding nucleoprotein (NP) an A virus. Focusing TDP-43, show it binds...
Significance Influenza viruses (IV) replicate in the nucleus. Export of newly produced genomes, packaged viral ribonucleoprotein (vRNP) complexes, relies on nuclear CRM1 export pathway and appears to be timely controlled by virus-induced cellular signaling. However, exact mechanism signaling-controlled complex assembly is enigmatic. Here we show that IV activates Raf/MEK/ERK/RSK1 pathway, leading phosphorylation at specific sites NP, which turn, creates a docking site for binding M1 protein,...
Effective drugs against SARS-CoV-2 are urgently needed to treat severe cases of infection and for prophylactic use. The main viral protease (nsp5 or 3CLpro) represents an attractive possibly broad-spectrum target drug development as it is essential the virus life cycle highly conserved among betacoronaviruses. Sensitive efficient high-throughput screening methods key discovery. Here we report a gain-of-signal, sensitive cell-based luciferase assay monitor nsp5 activity show that suitable...
During annual influenza epidemics, B viruses (IBVs) co-circulate with A (IAVs), can become predominant and cause severe morbidity mortality. Phylogenetic analyses suggest that IAVs (primarily avian viruses) IBVs human have diverged over long time scales. Identifying their common distinctive features is an effective approach to increase knowledge about the molecular details of infection. The virus-encoded RNA-dependent RNA polymerases (FluPolB FluPolA) are PB1-PB2-PA heterotrimers perform...
Out of the results sole large-scale screening for inhibitors SARS-CoV-1 main protease reported in 2013, attempts to improve 3-pyridyl-bearing hits found have been conducted research laboratories, either on this enzyme or more recently closely related SARS-CoV-2 protease. From resulting structural information reported, we sought design analogues featuring some components providing an affinity active site these proteases along with a different scaffold which would allow further...
Adaptation of avian influenza RNA polymerase (FluPol) to human cells requires mutations on the 627-NLS domains PB2 subunit. The E627K adaptive mutation compensates a 33-amino-acid deletion in acidic intrinsically disordered domain host transcription regulator ANP32A, that restricts FluPol activity mammalian cells. function ANP32A replication complex and particular its role restriction remains poorly understood. Here we characterize ternary complexes formed between FluPol, viral...
A naturally inspired chemical library of 25 molecules was synthesised guided by 3-D dimensionality and natural product likeness proved to have antiviral activity against SARS-CoV-2.
Abstract Replication of influenza viral RNA depends on at least two polymerases, a parental replicase and an encapsidase, cellular factor ANP32. ANP32 comprises LRR domain long C-terminal low complexity acidic region (LCAR). Here we show that is recruited to the replication complex (replicase-ANP32-encapsidase) by first acting as electrostatic chaperone stabilise encapsidase moiety within apo-polymerase symmetric dimers are distinct for A B polymerases. The with ANP32, then forms asymmetric...
Abstract Effective drugs against SARS-CoV-2 are urgently needed to treat severe cases of infection and for prophylactic use. The main viral protease (nsp5 or 3CLpro) represents an attractive possibly broad-spectrum target drug development as it is essential the virus life cycle highly conserved among betacoronaviruses. Sensitive efficient high-throughput screening methods key discovery. Here we report a gain-of-signal, sensitive cell-based luciferase assay monitor nsp5 activity show that...
ABSTRACT Recent technical advances have significantly improved our understanding of the RNA-binding protein (RBP) repertoire present within eukaryotic cells, with a particular focus on RBPs that interact cellular polyadenylated mRNAs. However, recent studies utilising same technologies begun to tease apart RBP interactome viral mRNAs, notably SARS-CoV-2, revealing both similarities and differences between profiles Herein, we comprehensively identified associate NP mRNA an influenza A virus....
ABSTRACT Adaptation of avian influenza RNA polymerase (FluPol) to human cells requires mutations on the 627-NLS domains PB2 subunit. The E627K adaptive mutation compensates a 33-amino-acid deletion in acidic intrinsically disordered domain host transcription regulator ANP32A, that restricts FluPol activity mammalian cells. function ANP32A replication complex and particular its role restriction remain poorly understood. Here we characterise ternary complexes formed between viral...
Abstract Influenza virus mRNA is stable and competent for nuclear export translation because it receives a 5′ cap(1) structure in process called cap-snatching 1 . During cap-snatching, the viral RNA-dependent RNA polymerase (FluPol) binds to host II (Pol II) emerging transcript 2,3 The FluPol endonuclease then cleaves capped fragment that sub-sequently acts as primer transcription of genes 4,5 Here, we present cryo-EM bound transcribing Pol complex with elongation factor DSIF pre-cleavage...
Abstract During annual influenza epidemics, B viruses (IBVs) co-circulate with A (IAVs), can become predominant and cause severe morbidity mortality. Phylogenetic analyses suggest that IAVs (primarily avian viruses) IBVs human have diverged over long time scales. Identifying their common distinctive features is an effective approach to increase knowledge about the molecular details of infection. The virus-encoded RNA-dependent RNA polymerases (FluPol FluPol ) are PB1-PB2-PA heterotrimers...
Summary The current model is that the influenza virus polymerase (FluPol) binds either to host RNA II (RNAP II) or acidic nuclear phosphoprotein 32 (ANP32), which drives its conformation and activity towards transcription replication of viral genome, respectively. Here, we provide evidence FluPol-RNAP binding interface has a so far overlooked function for genome. Using combination cell-based in vitro approaches, show RNAP C-terminal-domain, jointly with ANP32, enhances FluPol propose anchor...
Abstract Influenza polymerase, comprising subunits PA, PB1 and PB2, transcribes the negative-sense genomic viral RNA (vRNA) into mRNA or replicates it first complementary (cRNA) then back to vRNA. Here we investigate mechanism of de novo (unprimed) initiation vRNA cRNA replication. We present a high-resolution structure A/little-yellow-shouldered-bat/H17N10 polymerase with 3’ end template in synthesis active site, both apo-state after soaking GTP CTP. The priming incoming CTP are observed...
Abstract During influenza A virus (IAV) infections, viral proteins are targeted by cellular E3 ligases for modification with ubiquitin. Here, we decipher and functionally explore the ubiquitination landscape of IAV polymerase during infection human alveolar epithelial cells applying mass spectrometry analysis immuno-purified K-ε-GG (di-glycyl)-remnant-bearing peptides. We identified 59 modified lysines across all three subunits, PB2, PB1, PA, which 17 distinctively affected mRNA...