Mycobacterial evolution, physiology and virulence

Personnel involved

Principal investigators: Claude Gutierrez, Florence Levillain, Yannick Poquet

Other personnel: Pierre Dupuy, Wendy Le Mouellic, Bertille Voisin

Most mycobacteria are environmental species, causing disease only occasionally when they encounter a susceptible human or animal host. A few species, such as Mycobacterium tuberculosis, have become major pathogens during the course of evolution, and have acquired the ability to persist in their host despite natural or vaccine-induced immunity. Recent genomic studies by our lab and others provided evidence that early episodes of horizontal transfer of genomic islands from surrounding environmental species likely contributed to the evolution of M. tuberculosis towards a sophisticated human-adapted pathogen. We are currently deciphering the function of several of these genomic islands, including toxin-antitoxin systems, in mycobacterial metabolism and pathogenicity.

Horizontal acquisition of a group of molybdenum cofactor-encoding genes by the Mycobacterium tuberculosis ancestor from Burkholderia vietnamiensis or a close relative enabled M. tuberculosis to respond rapidly to hypoxic stress encountered in lung granuloma where it survives in a dormant state thanks to nitrate respiration. ©Françoise Viala
Distribution of zinc crystals (blacks dots) within macrophages and intraphagosomal M. tuberculosis.

In addition to comparative genomics, we exploit global gene expression profiling of host cell and mycobacterial responses to host-imposed stress. Dual host and pathogen DNA microarray analyses allowed to identify several families of eukaryotic and microbial genes whose expression is modulated upon infection. In particular, we recently identify a novel mechanism of innate immune control of pathogens through metal intoxication, and resistance strategies in pathogenic mycobacteria involving P-ATPases were discovered. We are currently deciphering the molecular and cellular mechanisms involved in microbial poisoning by zinc in infected macrophages, and the function of several P-ATPases in M. tuberculosis physiology and virulence. We also use dual RNA-seq analysis and Tn-seq analysis to understand M. tuberculosis adaptation to various host-imposed stresses, including hypoxia, and the role of metabolic circuits in mycobacterial response to stress.