Séminaire IRSD : Laurent Boyer

Laurent Boyer

Université Côte d’Azur, Inserm U1065, Team leader: Microbial Virulence and Inflammatory Signaling in Disease
Profil

The detection of the activities of pathogen-encoded virulence factors by the innate immune system has emerged as a new paradigm of pathogen recognition 1, 2. Much remains to be determined regarding the molecular components contributing to this defense mechanism in mammals and its importance during infection. Our team showed the central role of the IL-1β signaling axis in controlling the Escherichia coli burden in the blood in response to the sensing of the RhoGTPase-activating toxin CNF1 3. Using the CNF1 toxin, we provided evidence of the role of the NLRP3 inflammasome in sensing the activity of bacterial toxins and virulence factors that activates host RhoGTPases 4. We demonstrated that this activation relies on monitoring of the toxin’s activity on the RhoGTPase Rac2. We also showed that the NLRP3 inflammasome is activated by a signaling cascade involving the P21-activated kinases (Pak)-1/2 and the Pak1-mediated phosphorylation of Threonine 659 of NLRP3, which is necessary for the NLRP3-Nek7 interaction, the inflammasome activation and the IL-1ß cytokine maturation. Furthermore, inhibition of the Pak1-NLRP3 axis diminished the bacterial clearance of CNF1-expressing E. coli during bacteremia. Altogether, our results established Pak1/2 as critical regulators of the NLRP3 inflammasome and revealed the role of the Pak1-NLRP3 signaling axis in vivo during bacteremia 4,5. Building on this expertise, we set up an assay to quantify the NLRP3 activation in the blood of patients with bacteremia and applied it to COVID-19 patients. The analysis of the blood of 66 patients allowed us to reveal the heterogenous activation of NLRP3 in circulating myeloid cells during COVID-19 and predict severity 6.

• BOYER L, Magoc L, Dejardin S, Cappillino M, Paquette N, Hinault C, Charriere GM, Ip WK, Fracchia S, Hennessy E, Erturk-Hasdemir D, Reichhart JM, Silverman N, Lacy-Hulbert A, Stuart LM. (2011) Pathogen-Derived Effectors Trigger Protective Immunity via Activation of the Rac2 Enzyme and the IMD or Rip Kinase Signaling Pathway. Immunity, 35(4):536-49
• Stuart LM, Paquette N and BOYER L (2013) Effector-triggered versus pattern-triggered immunity: how animals sense virulent pathogens. Nature Reviews Immunology, 13(3):199-206
• Diabate M, Munro P, Garcia E, Jacquel A, Michel G, Obba S, Goncalves D, Luci C, Marchetti S, Demon D, Degos C, Bechah Y, Mege JL, Lamkanfi M, Auberger P, Gorvel JP, Stuart LM, Landraud L, Lemichez E and BOYER L. (2015) Escherichia coli alpha-Hemolysin counteracts the anti-virulence innate immune response triggered by the Rho GTPase activating toxin CNF1 during bacteremia. PLOS Pathogens
• Dufies O, Doye A, Courjon J, Torre C, Michel G, Loubatier C, Jacquel A, Chaintreuil P, Majoor A, Guinamard R. R, Gallerand A, Saavedra P.H.V., Verhoeyen E, Rey A, Marchett S, Ruimy R, Czerucka D, Lamkanfi M, Py B.F, Munro P, Visvikis O, BOYER L*. (2021) Escherichia coli RhoGTPase-activating toxin CNF1 mediates NLRP3 inflammasome activation via p21 activated kinases-1/2 during bacteremia in mice. Nature Microbiology
• Dufies O and BOYER L. (2021) RhoGTPases and inflammasomes: Guardians of effector-triggered immunity. PLOS Pathogens
• Courjon J, Dufies O, Robert A, Bailly L, Torre C, Chirio D, Contenti J, Vitale S, Loubatier C, Doye A, Pomares-Estran C, Gonfrier G, Lotte R, Munro P, Visvikis O, Dellamonica J, Giordanengo V, Carles M, Yvan-Charvet L, Ivanov S, Auberger P, Jacquel A, BOYER L. (2021) Heterogeneous NLRP3 inflammasome signature in circulating myeloid cells as a biomarker of COVID-19 severity. BLOOD Adv. Mar 9;5(5):1523-1534

Présentiel: Pavillon Beaudot

Cette présentation se dérouleront au Pavillon Baudot mais en raison de la situation sanitaire la jauge maximale est fixée à 30 personnes dans la salle de conférence.(Pass sanitaire obligatoire.), voir contact.
Le séminaire sera retransmis sur le lien teams des séminaires IRSD ci-dessous :
Séminaire L. Boyer : « Microbial virulence sensing by the innate immune system »

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Contact: Camille Chagneau