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Persistence and transmission of Mycobacterium tuberculosis

Principal Investigator: Christophe Guilhot (DR-CNRS)

 

The success of tubercle bacilli as pathogen relies mostly on its capacity to persist for decades in infected host and on its very high human-to-human transmission efficiency. There is a critical knowledge gap regarding the bacterial properties required for these steps of the infectious cycle. We use complementary approaches (genomic, genetic, lipidomic, cellular microbiology, & animal experimentation) to unveil the mycobacterial factors and metabolic adaptations required for persistence and transmission.

 

Field epidemiology studies has established that some phylogenetic lineages of tubercle bacilli, such as the Mycobacterium bovis or the Mycobacterium canettii strains, are impaired in their capacity to transmit in human. Recently, we have established that polymorphisms affecting the two component regulatory system PhoPR, modulates the virulence of M. bovis and explain the variability in the transmission capacity in humans. In parallel, we have contributed to demonstrate that the loss of a bacterial surface glycolipid enhances the virulence of M. canettii strains and was likely associated with the emergence of M. tuberculosis as major pathogen for humans.  We are pursuing these pioneering works with the aim to unravel the molecular bases of the transmission defect associated with some lineages and their consequences on the cross talk between the pathogen and the host.

In addition, we develop various genome-wide genetic screen and hypothesis-driven approaches to identify bacterial functions required for transmission. We look for M. tuberculosis genes controlling both the bacterial release in donor host and bacterial seeding in recipient host. For these approaches, we take advantage of our unique BSL3 facilities equipped with state-of-the art imaging systems to investigate mutant bacteria behavior in various cellular and animal models.

 

The expected results should shed light onto a crucial, but still unknown, step in tuberculosis and should help us to design strategy to block it.

 

Figure evol_0.jpg

Schematic phylogeny of tubercle bacilli with known or putative host. Mutations relevant for virulence and transmission capacity evolution uncovered in our studies are indicated.

Persons involved: 

Catherine Astarie-Dequeker (CR-CNRS)

Wladimir Malaga (IE-CNRS)

Delphine Payros (Post-Doc)

Arnaud Volle (IE-CDD)

Céline Berrone (AI-CDD).

Collaborations:

G. Fichant (LMGM, Toulouse), R. Brosch (Institut Pasteur, Paris), P. Brodin & P. Supply (Institut Pasteur, Lille), N. Winter (INRA, Tours), T. Wirth (Museum d’Histoire Naturelle, Paris), C. Martin (University Zaragoza, Spain).

Main publications and patents:

  • Boritsch et al.(2016) pks5-recombination-mediated cell surface remodelling in Mycobacterium tuberculosis emergence. Nature Microbiol. 1:15019.
  • Gonzalo-Asensio et al. (2014) Evolutionary history of tuberculosis shaped by conserved mutations in the PhoPR virulence regulator. Proc. Natl. Acad. Sci USA. 111:11491-11496.