Mycobacterial Interactions with Host Cells

The main goal of our research group is to better understand host-pathogen interactions in tuberculosis on the molecular and cellular levels, from the discovery of novel virulence genes in M. tuberculosis to the identification of immune mechanisms involved in host defense against the pathogen, with the overall objective of proposing better strategies to control disease.

We study host-pathogen interactions in tuberculosis, with a special interest in deciphering immunity to TB and the links between M. tuberculosis evolution, physiology and virulence.

Our research aims at exploring the links between metabolism and virulence in the TB bacillus, Mycobacterium tuberculosis, and how this link was shaped throughout evolution. In particular, we use dual global gene expression profiling (RNA-seq) and transposon mutant library screening (Tn-seq) to identify genes and pathways playing a part in host-pathogen interactions in TB. We especially identified a novel mechanism of innate immune control of pathogens through zinc intoxication, and resistance strategies in pathogenic mycobacteria involving P-ATPases were discovered. We are currently deciphering 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.

Our lab is also interested in understanding immunity to TB in absence and presence of co-infection with the AIDS virus HIV-1. In this context, we are deciphering the role of innate receptors, in particular C-type lectins, and host cell-expressed glycans in anti-mycobacterial immunity. As an example, we recently found that the C-type lectin DCIR modulates immunity to TB by sustaining type I interferon signaling in dendritic cells. The molecular mechanisms involved in DCIR signaling are being deciphered through biochemical and (phospho)proteomic experiments.
We are also exploring the role played by lymphocytes and innate lymphoid cells (ILCs) in immunity to TB. The contribution of ILCs to the immune response against M. tuberculosis is poorly known and our recent data indicate that TB infection induces some metabolism-driven phenotypic plasticity in the ILC compartment conferring an early protection against M. tuberculosis. Regarding other lymphocytes, we are currently developing imaging and functional approaches to understand which subpopulations of T lymphocytes have the best access, interaction and functional properties to reach M. tuberculosis infected cells.

Finally, in the context of TB/HIV co-infection, a predominant hypothesis to explain exacerbation of HIV-1 infection is that infection of macrophages by M. tuberculosis modulates the local inflammatory environments in favor of HIV-1 replication. We are currently exploiting different in vitro approaches to mimic this “bystander” effect emanating from sites of M. tuberculosis infection to dissect the molecular and cellular mechanisms rendering human monocytes and macrophages susceptible to HIV-1 infection. In parallel, within the context of co-infection in vivo, we establish crucial correlations of our in vitro findings in pulmonary lesions of non-human primates and human samples, including sera and pleural effusion fluid. Altogether, our ultimate goal is to deliver novel targets for diagnostic and therapeutic potential against co-morbidity established between AIDS and TB.

Team members

Research Scientists

Claude Gutierrez (University)
Denis Hudrisier (University)
Fabien Letisse (University)
Geanncarlo Lugo (CNRS)
Olivier Neyrolles (CNRS)
Yannick Poquet (University)
Yoann Rombouts (CNRS)

Research Engineers

Nelly Gilles
Florence Levillain (CNRS)
Bertille Voisin

Postdoctoral Fellows

Pierre Dupuy
Marion Faucher

PhD Students

Louis Benastre
Maxime Caouaille
Natacha Faivre
Wendy Le Mouellic
Sarah Monard
Stella Rousset

Our research projects

Boudehen*, Faucher* et al. (2022) Mycobacterial resistance to zinc poisoning requires assembly of P-ATPase-containing membrane metal efflux platforms. Nat Commun

Corral et al. (2022) ILC precursors differentiate into metabolically distinct ILC1-like cells during Mycobacterium tuberculosis infection. Cell Rep

Souriant et al. (2019) Tuberculosis exacerbates HIV-1 infection through IL-10/STAT3-dependent tunneling nanotube formation in macrophages. Cell Rep

Troegeler et al. (2017) C-type lectin receptor DCIR modulates immunity to tuberculosis by sustaining type I interferon signaling in dendritic cells. Proc Natl Acad Sci USA

Freire*, Gutierrez* et al. (2019) An NAD+ phosphorylase toxin triggers Mycobacterium tuberculosis cell death. Mol Cell

Levillain*, Poquet* et al. (2017) Horizontal acquisition of a hypoxia-responsive molybdenum cofactor biosynthesis pathway contributed to Mycobacterium tuberculosis pathoadaptation. PLOS Pathog

Confocal microscopy imaging of functional membrane micro domains (blue) in Mycobacterium tuberculosis © Y.-M. Boudehen