Pathogenesis of legionella
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.
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. Immun 2014).
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 (Michard et al. mBio 2015).
3- Identification of the Legionella Repeat-in Toxins (RTX) protein (RtxA) as a substrate of the Type 1 Secretion System (T1SS) (based on LssB, LssD and TolC proteins) and characterization of its role in the bacteria entry into the host cell (Fuche et al. Bacteriol. 2015).
4- 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 experimentally selected high-level macrolide-resistant clones that carry ribosomal mutations in 23S rRNA and L4 and L22 proteins (Descours G et al. Antimicrob Agents Chemother. 2017). We showed that mutations in non‑coding sequences upstream TolC-dependent efflux proteins encoding genes (lpeAB) result in upregulation of transcription of these genes and contribute to macrolide resistance (Massip et al. J Antimicrob Chemother. 2017). Interestingly, the presence of this efflux pump in specific Lp1 sequence types (ST) is correlated with higher MIC towards macrolides (Vandewalle-Capo M. et al., Int J Antimicrob Agents. 2017).
5- Epidemiological studies allowed the description of five clones of Lp1, spread worldwide and responsible of more than 40% of LD in Europe. Comparative genomic analyzes have shown that these clones have emerged worldwide, recently and independently, suggesting that humans have recently induced the emergence of new environmental niches facilitating this emergence. The clones associated with disease are linked by convergent evolution via recent recombination events. These analyses detected a region of 725 kb within five STs that could encode functions that allow them to be more virulent towards humans (David S. et al. Clin Infect Dis 2017; David et al. Genome Research 2016, Mentasti et al. Clin Microbiol Infect 2016, Valero et al. Genome Biol 2014).
INSERM, CNRS, Université Lyon 1, ANSES, ANR, Labex ECOFECT, Idex Université de Lyon (Breakthrough program).