Mycobacterial Interactions with Host Cells

Head : Olivier Neyrolles

Tuberculosis (TB) still kills more than 1.5 million people worldwide each year, and an estimated two billion individuals carry latent Mycobacterium tuberculosis infection. New drugs are urgently required to treat active and latent TB, and new vaccines are required for its prevention. One of the key features rendering the tubercle bacillus highly virulent is its ability to parasitize host phagocytic cells, including macrophages and dendritic cells in particular. The molecular mechanisms involved in this process have only recently been investigated, and host cell responses to M. tuberculosis infection, together with the microbial factors involved in intracellular survival, remain largely uncharacterized.

The Mycobacterial Interactions with Host Cells team has been launched in September 2007. Our laboratory is joined to the Sino-French Research Center in Life Sciences and Genomics in Shanghai, China, where Dr O. Neyrolles, Prof B. Gicquel and Prof J Zhang run the « M. tuberculosis genetic diversity and host-pathogen interactions » research team (http://www.rjh.com.cn/website/en/res.html). Our primary research goals aim at using a combination of functional genomics, cell biology and immunology approaches to improve our understanding of the subcellular and molecular mechanisms involved in immunity to M. tuberculosis and host cell parasitism by the tubercle bacillus.

Genome-wide identification and characterization of novel M. tuberculosis virulence factors involved in macrophage parasitism and phagosome remodeling

High-content visual analysis of a genome-covering M. tuberculosis mutant library screened at the whole cell and organelle levels in macrophages has allowed to identify a number of novel microbial genes involved in mycobacterial intracellular trafficking and host cell parasitism. In particular a novel locus involved in the synthesis and export of particular lipids of the mycobacterial cell envelope has been identified. The structure of these lipids together with their function in host cell infection and remodeling of the mycobacterial phagosome are currently being investigated.

Understanding the function of microbial and host cell transporters in mycobacterial interactions with host phagocytes

A recent global profiling study of host cell and mycobacterial responses to infection has allowed to identify several families of eukaryotic and microbial genes whose expression is modulated upon infection. In particular the expression of host cell and mycobacterial genes encoding various intracellular solute carriers has been found to be strongly altered during the infection process. The role of selected members of these transporter families in host-pathogen interactions is currently under investigation.

Deciphering the role of host cell surface receptors in M. tuberculosis entry and survival inside phagocytes

We have identified the C-type lectin DC-SIGN as a key M. tuberculosis receptor on the dendritic cells and alveolar macrophages of patients with TB. We have recently furthered our understanding of the role of DC-SIGN in TB, by investigating the function of selected mouse DC-SIGN homologues in experimental TB in mice, using various in vivo and in vitro systems.
We showed that the DC-SIGN murine homologue SIGNR3 mediates early protection against M. tuberculosis, through recognition of sugar motifs in the mycobacterial cell envelope and induction of protective cytokine secretion. C-type lectins and other mediators of innate and adaptive immunity to the TB bacillus are currently being investigated.