Presentation

LEGIOPATH Team

The Legiopath team, co-headed by Patricia Doublet and Sophie Jarraud, was created in 2013 at the same time of the CIRI. It is made up of eleven permanent researchers and around ten non-permanent staff (post-docs, doctoral and master's students, interns) bringing together complementary skills in microbiology, genetics, immunology and epidemiology. Our team is closely linked to the National Reference Center for Legionella (CNRL), also located in Lyon, which is headed by Sophie Jarraud.

General interests

Legionella pneumophila serogroup 1 (Lp1) is the etiologic agent of Legionnaires’ disease (LD), a severe community or hospital-acquired pneumonia that is associated to an overall high, but variable case mortality rate between 10% to 30% of cases. LD is emerging as a public health concern when considering the highest never observed rates of LD since 2017 in Europe and France, and the high mortality rate despite appropriate antibiotics treatment. Our final objective is to characterize the bacterial, host and environmental determinants of the acquirement and the severity of legionellosis in order to contribute to a better and more efficient care of the patients. In that purpose, we benefit from biological and clinical data from the French National Reference Center for Legionella (NRCL) and we are developing an integrated strategy from the study of molecular mechanisms of bacteria-host cell interactions, physiopathology of LD in mouse and human cell models to clinical microbiology of human LD. In collaboration, we are also including some environmental parameters such as pollution in our research project.

Main Achievements

1. Demonstration that the translocation of the 300 Type 4 Secretion System (T4SS) Dot/Icm effectors is finely orchestrated, in a cyclic-diGMP dependent manner, and this control is required for efficient infection (Allombert et al. Infect. Immun, 2014; Allombert et al. J. Mol. Biol., 2021).

2. Identification of the role of LegK2, a T4SS Dot/Icm effector, in host cell infection: LegK2 phosphorylates the ARP3 and ARPC1b subunits of the actin nucleator, which results in inhibition of ARP2/3-mediated actin polymerization at the surface of the Legionella containing vacuole (LCV), and subsequently in inhibition of late endosomes trafficking towards the LCV (Pillon et al. Cell. Microbiol. 2024 ; Michard et al. mBio 2015).

3. Investigation of the hypothesis according to which therapeutic failures in patients could be due to Lp1 resistance to macrolides, the first-line therapy for the treatment of LD. We selected lineages of high-level macrolide-resistant Lp with mutations in 23S rRNA, L4 and L22 proteins (Descours, Antimicrob Agents Chemother 2017), and in non‑coding sequences upstream TolC-dependent efflux proteins encoding genes (Massip, J Antimicrob Chemother. 2017; Vandewalle-Capo, Int J Antimicrob Agents 2017). 

4. Although macrolide-resistant strains have been recently identified in the environment (Portal, J Antimicrob Chemother 2021; Ginevra, J Antimicrob Chemother 2022), no clinical resistance has been reported, suggesting that recalcitrant LD is most likely due to Lp persisters (Pouderoux, Clin Infect Dis. 2020; Adams-Ward, Front Cell Infect Microbiol 2023).

5. Investigation of host Immune response to clinical isolates. In human macrophages infection, we demonstrated that clinically relevant Lp isolates displayed TNF secretion and TNF-induced cell death according to their genotypes (Guillemot, Virulence 2022). 

6. Global understanding of pathophysiology of severe LD. By the coordination of a national prospective interventional ProgLegio study (NCT03064737), we showed that severe LD is associated with impairments immune response with a hyper-inflammatory phase in the early phase of Lp pneumonia and a leukocyte immunoparalysis for a large number of cytokines (Allam, Front. Cell Infect Microbiol. 2023; Pérez -Cobas, Cell. Rep. Med. 2023 & mBio 2020) 

Sponsors: INSERM, CNRS, Université Lyon 1, ANSES, ANR, Labex ECOFECT, Idex Université de Lyon (Breakthrough program).