Published on December 14, 2018 | Updated on December 14, 2018


Pinpointing virulence genetic variants diversity of Mycobacterium tuberculosis and pathogen community composition

Co-leaders : Jean-Luc Berland (CIRI) & Samuel Venner (LBBE)

Tuberculosis caused by Mycobacterium tuberculosis (MTB) complex remains a deadly infectious diseases worldwide. MTB infection results in a variety of disease manifestations and epidemiological success: latent asymptomatic infection and/or progression to pulmonary or extra-pulmonary injuries, with an array of severity symptoms. Such diversity has been historically attributed to host and environmental factors, while the MTB complex was previously considered genetically monomorphic: it is thought to have evolved by clonal expansion from a progenitor infecting mammalians and to have since co-evolved in hosts. Without any evidence for on-going horizontal gene exchange in MTB, lineage specificities are mostly confined to sets of mutations. But up to now there are no proven genetic determinants of its virulence: disease progression, severity, or spreading success. Towards the general objective to pinpoint these putative genetic determinants of clinical pathophysiology and epidemiological features, we propose to combine conventional microbiology, statistics and community ecology concepts to get insight on the involvement of pathogen genetic in MTB manifestations.
Recently, studies based on Whole Genome Sequencing have revealed micro-diversity in isolates composition: within hosts, minor variants coexist rather than a clonal colony. But this diversity and its dynamics have not yet been considered as a source of information to highlight the process leading to adapt and respond to a changing environment. The work package 1 will first, gather information on genomic micro-diversity from a collection of well described MTB isolates covering representatives of the global lineages, clinical presentations variety, together with their related clinical metadata. Second, stemmed from this information, describe the patterns of genomic variant assemblages at several scales, characteristics and their relative abundance. To result in the inference of the ecological process potentially at the origin of the observed diversity: determinist, stochastic, dispersal, and degree of innovation. The work package 2 will assess the performances of genetic variants and variant assemblages in a controlled environment, an in vitro infection model, to capture virulence genetic determinant candidates by statistical correlating variant presence and clinical presentation / pathophysiology / epidemic success in host individuals; and in parallel, through competitive assays, the drivers of the dynamics of MTB community to inform either on a determinist process or on a stochastic demography dynamics.
Thus, by analyzing diversity and performances of genetic variants obtained from Rhone-Alpes isolates collection and understanding the community ecology of this pathogens, we aim to capture some determinants or process leading to pathogen virulence. In a long term view, models stemmed from this research work axis (e.g. stochastic host-pathogen metacommunity models) could be expanded to study the dynamics of other diseases beyond TB, with etiologic agents displaying communities of variants and infecting populations or communities of hosts.

Co-leaders : Jean-Luc Berland, team "Laboratoire des pathogènes émergents - Fondation Mérieux" (CIRI) & Samuel Venner, team "Ecologie Quantitative et Evolutive des Communautés" (LBBE).
Collaborative teams: Oana Dumitrescu , team "Pathogénie des staphylocoques" (CIRI) & Laurent Jacob, team "Statistique en grande dimension pour la génomique" (LBBE).
Project duration :
2 years
Financing :
Post-doctoral fellowship & consumable money
Post-doctoral fellow:
Charlotte Genestet