Autophagie, Infections et Immunité

 

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Recent achievements

Basic research

Macroautophagy, referred to as autophagy, is an instrumental process for the maintenance of cellular homeostasis whose regulation/execution relies on AuTophaGy-related (ATG) proteins and dozens of autophagy-associated proteins in mammalian cells. It allows for the degradation and recycling of cytosplasmic components at steady state and in response to changes in the microenvironment. Autophagy also contributes to cellular defense against intracellular microbes. The importance of autophagy in pathophysiological processes was highlighted by the 2016 Nobel prize.

The targeting of cargos to nascent autophagosomes involves specialized factors called autophagy receptors. Once constituted, cargo-containing vesicles (autophagosomes) undergo fusion with vesicles of the endo-lysosomal compartment (maturation) leading to degradation of the content within autolysosomes.

Regulation of autophagy upon infection.

* The team identified the first human pathogen receptor, which is directly connected to the autophagy machinery upon infection and described the molecular pathway involved (Joubert et al. Cell Host & Microbe, 2009).

* The team reported the first RNA virus/autophagy protein-protein interactome and identified a common molecular strategy used by several RNA viruses to manipulate autophagy (Grégoire et al. PloS Pathogens, 2011).

* The team have shown that three successive but independent signals of autophagy can be induced upon infection by a virus, the measles virus (MeV), what delays infection-induced cell death (Richetta et al. PloS Pathogens, 2013).

* The team was the first to report, and to characterize, an unappreciated dual role for the autophagy receptors NDP52 and OPTN (but not p62) which, apart from targeting bacteria to growing autophagosomal membranes, promote the maturation of bacteria-containing autophagosomes, thereby facilitating pathogen degradation (Verlhac et al. Cell Host & Microbe, 2015).

* We reported that measles virus could specifically targets certain autophagy receptors involved in autophagosome maturation (NDP52 and T6BP, but not OPTN) in order to efficiently replicate within infected cells and described T6BP as another autophagy receptor able to regulate autophagosome maturation (Petkova et al. Viruses, 2017).

Clinical/Translational research

Crohn’s Disease is a chronic intestinal inflammatory disorder affecting around 1 million people in Europe. Current models for pathogenesis propose that Crohn’s Disease results from inappropriate and sustained immune responses towards the luminal flora in genetically susceptible hosts. Genomic analyses had revealed a high association between Crohn’s Disease susceptibility and polymorphisms affecting autophagy-related genes.

Surrogate biomarkers for predicting CD patient response to biotherapy.

 

* we determined that the monitoring of fecal calprotectin concentrations is a useful tool to detect postoperative endoscopic recurrence in asymptomatic CD patients after ileocolic resection, what has importance to avoid ileocolonoscopies in 30% of patients (Am J Gastroenterol, 2015).

* we demonstrated that the response to anti-TNFa therapy can be predicted by following various surrogate markers such as M2-Pyruvate Kinase (a cytosolic enzyme involved in glycolysis), fecal lactoferrin, calprotectin (Inflamm Bowel dis 2015; Dig. Liv. Dis., 2017) and investigated the relationships between the titer of anti-glycans specific antibodies and the severity of CD (J Crohn’s Colitis 2015).

* we monitored levels of inflammatory biomarkers and drug in CD patients treated with specific anti-IL12p40mAbs (ustekinumab) and identified the relationship between drug concentration and therapeutic response and propose a cut-off to distinguish early primary non-responder to responder patients during induction therapy, what contribute to establish new algorithm of treatment and to develop personalized medicine (Clin. Gastro. Hep., 2019).

 

PRINCIPALES PUBLICATIONS

For the full updated list of publications see:

M Faure : GoogleScholar CV

Soufflet N, Boschetti G,Roblin X, Cuercq C, Williet N, Charlois AL, Duclaux-Loras R, Danion P, Mialon A, Faure M, Paul S, Flourie B, Nancey S(2019). Concentrations of Ustekinumab During Induction Therapy Associate With Remission in Patients With Crohn’s Disease. Clin Gastroenterol Hepatol. Mar; pii: S1542-3565(19)30248-4.

Allez M, Auzolle C, Ngollo M, Bottois H, Chardiny V, Corraliza AM, Salas A, Perez K, Stefanescu C, Nancey S, Buisson A, Pariente B, Fumery M, Sokol H, Tréton X, Barnich N, Seksik P, Le Bourhis L,…,Boschetti G, Flourié B.. REMIND Study Group (2019). T cell clonal expansions in ileal Crohn’s disease are associated with smoking behaviour and postoperative recurrence. Gut. Feb 12.

Viret C, Faure M.(2019). Regulation of Syntaxin 17 during Autophagosome Maturation. Trends Cell Biol.Jan;29(1):1-3 Spotlight.

Roblin X, Vérot C, Paul S, Duru G, Williet N, Boschetti G, Del Tedesco E, Peyrin-Biroulet L, Marc Phelip J, Nancey S, Flourie B(2018). Is the Pharmacokinetic Profile of a First Anti-TNF Predictive of the Clinical Outcome and Pharmacokinetics of a Second Anti-TNF? Inflamm Bowel Dis.Apr;224(9):2078-85.

Viret C, Rozières A, Faure M(2018). Autophagy during Early Virus-Host Cell Interactions. J Mol Biol. 2018 Jun;430(12):1696-1713.

Viret C, Rozières A, Faure M(2018). Novel Insights into NDP52 Autophagy Receptor Functioning. Trends Cell Biol. Apr;28(4):255-257 Spotlight.

Petkova DS, Verlhac P, Rozières A, Baguet J, Claviere M,Kretz-Remy C, Mahieux R,Viret C, Faure M(2017). Distinct Contributions of Autophagy Receptors in Measles Virus Replication. Viruses. May; 9(5).

Frin AC, Filippi J, Boschetti G, Flourie B,Drai J, Ferrari P, Hebuterne X, Nancey S(2017). Accuracies of fecal calprotectin, lactoferrin, M2-pyruvate kinase, neopterin and zonulin to predict the response to infliximab in ulcerative colitis. Dig Liver Dis. Jan;49(1):11-16.

Rozières A, Viret C, Faure M(2017). Autophagy in Measles Virus Infection. Viruses.Nov;9(12).

Venturin C, Nancey S,Danion P, Uzzan M, Chauvenet M, Bergoin C, Roblin X, Flourié B, Boschetti G(2017). Fetal death in utero and miscarriage in a patient with Crohn’s disease under therapy with ustekinumab: case-report and review of the literature. BMC Gastroenterol. Jun 19;17(1):80.

Verlhac P, Grégoire IP, Azocar O, Petkova DS, Baguet J, Viret C and M. Faure(2015). Regulation of Autophagosome Maturation by NDP52 is Required for Selective Pathogen Degradation by Autophagy. Cell Host & Microbe. Apr; V17(4):515-25.

Boschetti G, Laidet M, Moussata D, Stefanescu C, Roblin X, Phelip G, Cotte E, Passot G, Francois Y, Drai J, Del Tedesc E, Bouhnik Y, Flourie B, Nancey S(2015). Levels of Fecal Calprotectin Are Associated With the Severity of Postoperative Endoscopic Recurrence in Asymptomatic Patients With Crohn’s Disease. Am J Gastroenterol. Jun;110(6):865-72.

Verlhac P, Viret C, Faure M (2015). Dual function of CALCOCO2/NDP52 during xenophagy. Autophagy. 11(6):965-6. Editorial Material.

Verlhac P, Viret C, Faure M(2015). Handcuffs for bacteria – NDP52 orchestrates xenophagy of intracellular Salmonella. Microb Cell. May;2(6):214-215.

Faure M(2014).The p value of HPIV3-mediated autophagy inhibition.Cell Host Microbe. May;15(5):519-21 Preview.

Richetta C, Grégoire IP, Verlhac P, Azocar O, Baguet J, Flacher M, Tangy F, Rabourdin-Combe C, FaureM(2013). Sustained autophagy contributes to measles virus infectivity. PLoS Pathog. 2013;9(9):e1003599.

Faure M, Lafont F (2013). Pathogen-induced autophagy signaling in innate immunity. J Innate Immun. 5(5):456-70. doi: 10.1159/000350918.

Petkova DS, Viret C, Faure M(2013). IRGM in autophagy and viral infections. Front Immunol. Jan 17;3:426.

Richetta C, Faure M(2013). Cell Microbiol. Autophagy in antiviral innate immunity. Mar;15(3):368-76. doi: 10.1111/cmi.12043. review

Grégoire IP, Rabourdin-Combe C, Faure M(2012). Autophagy and RNA virus interactomes reveal IRGM as a common target. Autophagy. Jul 1;8(7):1136-7. doi: 10.4161/auto.20339. Epub 2012 Jun 22.

Faure M, Rabourdin-Combe C (2011). Innate immunity modulation in virus entry. Curr Opin Virol. Jul;1(1):6-12. doi: 10.1016/j.coviro.2011.05.013. Epub 2011 Jul 4. Review.

Grégoire IP, Richetta C, Meyniel-Schicklin L, Borel S, Pradezynski F, Diaz O, Deloire A, Azocar O, Baguet J, Le Breton M, Mangeot PE, Navratil V, Joubert PE, Flacher M, Vidalain PO, André P, Lotteau V, Biard-Piechaczyk M, Rabourdin-Combe C, Faure M(2011).IRGM is a common target of RNA viruses that subvert the autophagy network. PLoS Pathog. Dec;7(12):e1002422. doi: 10.1371/journal.ppat.1002422. Epub 2011 Dec 8.

Meiffren G, Joubert PE, Grégoire IP, Codogno P, Rabourdin-Combe C, Faure M(2010). Pathogen recognition by the cell surface receptor CD46 induces autophagy. Autophagy. Feb;6(2):299-300

Joubert PE, Meiffren G, Grégoire IP,Pontini G, Richetta C, Flacher M, Azocar O, Vidalain PO, Vidal M, Lotteau V, Codogno P, Rabourdin-Combe C, Faure M(2009). Autophagy induction by the pathogen receptor CD46.Cell Host Microbe. Oct 22;6(4):354-66.