Blanc SVSE 3 - Blanc - SVSE 3 - Microbiologie, immunologie, infectiologie

Epigenetic reprogramming by the pathogenic bacterium Listeria monocytogenes – EPILIS

Gene reprogramming in cells infected with the bacterial pathogen Listeria.

During an infection, pathogenic bacteria must circumvent host immune responses in order to colonize its host. The EPILIS project studies how Listeria, the causative agent of human listeriosis, modulates the chromatin present in the nucleus of the infected cell in order to reprogram immune genes to its advantage.

Epigenetics and infection; towards a better understanding and cure for infectious diseases

It is a priority to characterize, during infection, the molecules that are important for regulating specific genes and to identify which factors alter and are the cause of observed pathologies. Bacterial pathogens can interfere with host nuclear proteins and modify the expression of genes important for defense against infection. The EPILIS project aims to elucidate the molecular bases of these mechanisms through a characterization of the bacterial proteins and host factors involved in epigenetic reprogramming induced by bacterial pathogens.

To achieve the goals of this project, we are using and developing cutting edge technologies, such as chromatin immunoprecipitation coupled to deep sequencing, purification of chromatin-associated complexes, and crystallography followed by 3D structure determination. We are also using mice lines, which bear mutations in chromatin regulatory genes, in order to study the mechanisms of infection in vivo.

(1) We have identified « nucleomodulins », bacterial proteins that are secreted by intracellular bacteria and target the infected cell’s nucleus to pertubate transcription or RNA maturation. (2) We have identified chromatin factors involved in baterial infections. (3) Finally, we have characterized new virulence mechanisms important for bacterial infections.

Our results point to a role of epigenetic regulation (changes in gene expression which take place without altering the DNA sequence) during an infection by Listeria. We are currently investigating whether an epigenetic memory of infection could exist in a host which is no longer infected. This discovery, if proven for other pathogens as well, would contribute to a better understanding of infectious diseases and provide information on how best to combat them.

Our work has revealed new immunity genes activated during infection with major pathogens such as those responsible for listeriosis, staphylococcus infections and tuberculosis:
Bierne H., Travier L., Mahlakõiv T., Tailleux L, Subtil A., Lebreton A., Paliwal A., Gicquel B., Staeheli P., Lecuit M. and P. Cossart. 2012. Activation of Type III Interferon Genes by Pathogenic Bacteria in Infected Epithelial cells and Mouse Placenta. PLoS ONE. Volume 7 | Issue 6 | e39080.
The scientific bases of the EPILIS project are discussed in three revues:
Lebreton A, Cossart P and H. Bierne. 2012. Bacteria tune interferon responses by playing with chromatin. Virulence. 1;3(1):87-91.
Bierne H, Cossart P. 2012. When bacteria target the nucleus: the emerging family of nucleomodulins. Cell Microbiol. 14(5):622-33.
Hamon MA, Ribet D, Stavru F, Cossart P. Listeriolysin O: the Swiss army knife of Listeria. Trends Microbiol. 2012 may 2012

Chromatin modifications, at the level of either histones or cytosines present in DNA, are fundamental regulators of gene expression in eukaryotes as they control the access of the transcriptional machinery to the targeted promoter regions. When these modifications are transmitted during mitosis, they reprogram the daughter cells without altering the genomic sequence, a process termed « epigenetic ». Recent studies have found that chromatin modifications are induced by bacterial pathogens to interfere with the host transcriptional program. However, the mechanisms at play are poorly characterized. Our project is centered on this new facet of host-pathogen interactions. In line with our published work, we will study the chromatin modifications induced by the intracellular bacterial pathogen Listeria monocytogenes, for which we have identified and gathered preliminary data on several factors targeting chromatin. These factors act by two different strategies:
- through activation of specific signalling cascades;
- through direct control of chromatin regulators.
In this project, we plan to elucidate the molecular basis of these new mechanisms by characterizing bacterial proteins, host factors, chromatin marks and genes reprogrammed. Furthermore, we will determine whether DNA methylation or histone modification profiles imposed by bacterial factors are maintained over time, as chromatin modifications (and parallel gene expression) may be transmitted to daughter cells during cell division. This would imply that an infection leaves an epigenetic mark after pathogen eradication, establishing a memory of infection in parallel to acquired immunity. Besides direct obvious implications of such a discovery on public health, it could shed light on possible mechanisms at play in the etiology of certain unexplained affections, such as autoimmune diseases or certain cancers, via bacterial-mediated epigenetic dysregulation of immune responses.

To achieve the goals proposed in this project, we will use cutting-edge technologies, such as chromatin/methyl DNA immunoprecipitation followed by deep sequencing, RNAi screening, tandem affinity purification of chromatin complexes and X-ray crystallography. In addition, this project will greatly benefit from the complementary expertise of the four teams involved (microbiology, cellular biology, genomics, epigenetics/chromatin biochemistry and structural biology), the high quality of the infrastructures, and the numerous tools (stable cell lines, bacterial mutants, purified proteins, knock-out mice), which will guarantee advances in the field. All the elements converge for the success of this project.

Project coordination

BIERNE Hélène (Organisme de recherche)

The author of this summary is the project coordinator, who is responsible for the content of this summary. The ANR declines any responsibility as for its contents.



Help of the ANR 580,000 euros
Beginning and duration of the scientific project: September 2011 - 36 Months

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