Research Interests - Alice Lebreton-Mansuy
Ph.D. - INRA research Scientist
I am working in the group “Nuclear Signaling, Epigenetics and Infection” nucleated by Hélène Bierne. Since I joined the lab in 2008, my research focuses on deciphering the molecular mechanisms by which Listeria monocytogenes modulates host type-III interferon (IFN-λ) response by subverting chromatin silencing.
LntA, a virulence factor secreted by Listeria and targeting the host cell nucleus
Hélène Bierne initiated the characterization of a new virulence factor of Listeria monocytogenes, LntA, revealed by post-genomic studies. Bacteria secrete this small, basic protein, during the infection process. It is then targeted to the nucleus of host cells, where it interacts with a chromatin protein, BAHD1, and regulates the transcription of host genes.
We have shown that, when Listeria monocytogenes infects epithelial cells, it can induce the type III interferon pathway, leading to the activation of a set of immunity genes, Interferon Stimulated Genes (ISGs). However, the infection also triggers the repression of these genes by the BAHD1 chromatin-silencing complex.
When intracellular bacteria secrete LntA, it enters the nucleus of infected cells and alleviates the action of the BAHD1 complex; thereby, LntA activates ISGs. These mechanisms enable Listeria to either stimulate or suppress the type-III interferon pathway along the infectious process.
lntA, a tightly controlled virulence gene
During our previous works, we have we have observed that the lntA gene expression was tightly locked in most conditions, which probably prevents inappropriate activation of host defences and subsequent bacterial clearance.
I am now trying to unravel the lntA regulation mechanisms, and to define precisely when and where lntA expression is turned on during the infectious process. This should provide a better understanding of the reasons why Listeria needs to activate IFN-λ response for efficient listeriosis.
In parallel, I keep on characterizing in details the mechanisms of LntA-mediated regulation of ISGs, by studying the pattern of chromatin modifications and its consequences on the outcome of infection. This is necessarily intimately linked to in-depth studies of LntA human partner, BAHD1, both in vivo and in vitro. Additionally, in collaboration with Viviana Job and Andréa Dessen at the Institut de Biologie Structurale (Grenoble), who solved the structure of LntA by crystallography, I am deciphering the molecular determinants required for a functional LntA-BAHD1 interaction.