Antibiotics have revolutionized modern medicine but antibiotic resistance is an increasing threat to health, compromising the ability to treat bacterial infections and to carry out medical procedures, including chemotherapy, transplants, and surgery. The National, and International action plans demonstrate the necessity to develop innovative research to stop the progression of resistance in community-acquired and care-related bacterial infections. Antibiotics are uniquely considered as direct antimicrobial agents, and most efficacy evaluations are based on in vitro assays or immunosuppressed animals. However, there are several pieces of evidence that host immunity contributes to the efficacy of the antibiotic treatment. Thus, antibiotics by reducing the amount of the pathogenic bacteria, by modifying their virulence factors, and by killing/inactivating bacteria likely regulate the antibacterial immune responses. Deciphering the nature of cellular and molecular immune effectors contributing to antibiotic activity will open avenues to innovative approaches to combat infections with multidrug-resistant bacteria.
The team will promote two main research axes covering basic research to clinical research:
- Development of inhaled flagellin as an adjunct therapy in bacterial pneumonia (https://fair-flagellin.eu)
- Identification of immune correlates of protection throughout the differentiation and function of myeloid cells in the context of antibiotic treatment of bacterial infections
Jean-Claude Sirard received his PhD degree in 1995 from the University of Paris and the Pasteur Institute. Between 1991 and 1998, he studied bacterial pathogenesis of Bacillus anthracis, the causative agent of anthrax. He trained as a postdoctoral fellow between 1998 and 2003 at the Swiss Experimental Research Center on Cancer (ISREC) in Lausanne working on the interaction of intestinal epithelial cells with bacterial pathogens such as Salmonella enterica. He has been a pioneer in identifying flagellin as a major bacterial component that triggers pro-inflammatory responses in mammals. In 2003, he joined the Institut Pasteur de Lille as a laureate of the Young Investigator program ATIPE/AVENIR and he obtained a tenure position at Inserm to develop a research on epithelial innate immunity. The team led by Jean-Claude Sirard investigates the role of immune cells and immune mediators in host defense during respiratory infections by pathogenic bacteria, especially antibiotic-resistant Streptococcus pneumoniae and Klebsiella pneumoniae. The team aims at developing new adjuvants to trigger respiratory innate immunity in prophylaxis and therapeutic settings.
Vijayan, A., L. Van Maele, D. Fougeron, D. Cayet, and J. C. Sirard. 2020. The GM-CSF Released by Airway Epithelial Cells Orchestrates the Mucosal Adjuvant Activity of Flagellin. J Immunol.
Liu, X., J. M. Kimmey, L. Matarazzo, V. de Bakker, L. Van Maele, J. C. Sirard, V. Nizet, and J. W. Veening. 2020. Exploration of Bacterial Bottlenecks and Streptococcus pneumoniae Pathogenesis by CRISPRi-Seq. Cell Host Microbe.
Van Maele, L., D. Fougeron, D. Cayet, A. Chalon, D. Piccioli, C. Collignon, J. C. Sirard, and A. M. Didierlaurent. 2019. Toll-like receptor 4 signaling in hematopoietic-lineage cells contributes to the enhanced activity of the human vaccine adjuvant AS01. Eur J Immunol 49: 2134-2145.
Matarazzo, L., F. Casilag, R. Porte, F. Wallet, D. Cayet, C. Faveeuw, C. Carnoy, and J. C. Sirard. 2019. Therapeutic Synergy Between Antibiotics and Pulmonary Toll-Like Receptor 5 Stimulation in Antibiotic-Sensitive or -Resistant Pneumonia. Front Immunol 10: 723.
Georgel, A. F., D. Cayet, A. Pizzorno, M. Rosa-Calatrava, C. Paget, V. Sencio, J. Dubuisson, F. Trottein, J. C. Sirard, and C. Carnoy. 2019. Toll-like receptor 5 agonist flagellin reduces influenza A virus replication independently of type I interferon and interleukin 22 and improves antiviral efficacy of oseltamivir. Antiviral Res 168: 28-35.
Biedma, M. E., D. Cayet, J. Tabareau, A. H. Rossi, K. Ivicak-Kocjan, G. Moreno, A. Errea, D. Soulard, G. Parisi, R. Jerala, P. Berguer, M. Rumbo, and J. C. Sirard. 2019. Recombinant flagellins with deletions in domains D1, D2, and D3: Characterization as novel immunoadjuvants. Vaccine 37: 652-663.
Vijayan, A., M. Rumbo, C. Carnoy, and J. C. Sirard. 2018. Compartmentalized Antimicrobial Defenses in Response to Flagellin. Trends Microbiol 26: 423-435.
Beshara, R., V. Sencio, D. Soulard, A. Barthelemy, J. Fontaine, T. Pinteau, L. Deruyter, M. B. Ismail, C. Paget, J. C. Sirard, F. Trottein, and C. Faveeuw. 2018. Alteration of Flt3-Ligand-dependent de novo generation of conventional dendritic cells during influenza infection contributes to respiratory bacterial superinfection. PLoS Pathog 14: e1007360.
Porte, R., L. Van Maele, N. Munoz-Wolf, B. Foligne, L. Dumoutier, J. Tabareau, D. Cayet, P. Gosset, N. Jonckheere, I. Van Seuningen, J. A. Chabalgoity, M. Simonet, M. Lamkanfi, J. C. Renauld, J. C. Sirard, and C. Carnoy. 2017. Flagellin-Mediated Protection against Intestinal Yersinia pseudotuberculosis Infection Does Not Require Interleukin-22. Infect Immun 85.
Ghinnagow, R., J. De Meester, L. J. Cruz, C. Aspord, S. Corgnac, E. Macho-Fernandez, D. Soulard, J. Fontaine, L. Chaperot, J. Charles, F. Soncin, F. Mami-Chouaib, J. Plumas, C. Faveeuw, and F. Trottein. 2017. Co-delivery of the NKT agonist alpha-galactosylceramide and tumor antigens to cross-priming dendritic cells breaks tolerance to self-antigens and promotes antitumor responses. Oncoimmunology 6: e1339855.
Ghinnagow, R., L. J. Cruz, E. Macho-Fernandez, C. Faveeuw, and F. Trottein. 2017. Enhancement of Adjuvant Functions of Natural Killer T Cells Using Nanovector Delivery Systems: Application in Anticancer Immune Therapy. Front Immunol 8: 879.
Barthelemy, A., S. Ivanov, J. Fontaine, D. Soulard, H. Bouabe, C. Paget, C. Faveeuw, and F. Trottein. 2017. Influenza A virus-induced release of interleukin-10 inhibits the anti-microbial activities of invariant natural killer T cells during invasive pneumococcal superinfection. Mucosal Immunol 10: 460-469.
Porte, R., D. Fougeron, N. Munoz-Wolf, J. Tabareau, A. F. Georgel, F. Wallet, C. Paget, F. Trottein, J. A. Chabalgoity, C. Carnoy, and J. C. Sirard. 2015. A Toll-Like Receptor 5 Agonist Improves the Efficacy of Antibiotics in Treatment of Primary and Influenza Virus-Associated Pneumococcal Mouse Infections. Antimicrob Agents Chemother 59: 6064-6072.
Fougeron, D., L. Van Maele, P. Songhet, D. Cayet, D. Hot, N. Van Rooijen, H. J. Mollenkopf, W. D. Hardt, A. G. Benecke, and J. C. Sirard. 2015. Indirect Toll-like receptor 5-mediated activation of conventional dendritic cells promotes the mucosal adjuvant activity of flagellin in the respiratory tract. Vaccine 33: 3331-3341.
Van Maele, L., D. Fougeron, L. Janot, A. Didierlaurent, D. Cayet, J. Tabareau, M. Rumbo, S. Corvo-Chamaillard, S. Boulenouar, S. Jeffs, L. Vande Walle, M. Lamkanfi, Y. Lemoine, F. Erard, D. Hot, T. Hussell, B. Ryffel, A. G. Benecke, and J. C. Sirard. 2014. Airway structural cells regulate TLR5-mediated mucosal adjuvant activity. Mucosal Immunol 7: 489-500.
Van Maele, L., C. Carnoy, D. Cayet, S. Ivanov, R. Porte, E. Deruy, J. A. Chabalgoity, J. C. Renauld, G. Eberl, A. G. Benecke, F. Trottein, C. Faveeuw, and J. C. Sirard. 2014. Activation of Type 3 innate lymphoid cells and interleukin 22 secretion in the lungs during Streptococcus pneumoniae infection. J Infect Dis 210: 493-503.
Macho-Fernandez, E., L. J. Cruz, R. Ghinnagow, J. Fontaine, E. Bialecki, B. Frisch, F. Trottein, and C. Faveeuw. 2014. Targeted delivery of alpha-galactosylceramide to CD8alpha+ dendritic cells optimizes type I NKT cell-based antitumor responses. J Immunol 193: 961-969.
Faveeuw, C., and F. Trottein. 2014. Optimization of natural killer T cell-mediated immunotherapy in cancer using cell-based and nanovector vaccines. Cancer Res 74: 1632-1638.