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Updated: Aug 2, 2025
Tractable Mammalian Cell Infections with Protozoan-primed Bacteria
Published on: April 2, 2013
Legionella para-effectors target chromatin and promote bacterial replication
Daniel Schator1,2,3, Sonia Mondino1,4, Jérémy Berthelet5,6
1Institut Pasteur, Université Paris Cité, CNRS UMR 6047, Biologie des Bactéries Intracellulaires, 75015, Paris, France.
Abstract:
Legionella pneumophila replicates intracellularly by secreting effectors via a type IV secretion system. One of these effectors is a eukaryotic methyltransferase (RomA) that methylates K14 of histone H3 (H3K14me3) to counteract host immune responses. However, it is not known how L. pneumophila infection catalyses H3K14 methylation as this residue is usually acetylated. Here we show that L. pneumophila secretes a eukaryotic-like histone deacetylase (LphD) that specifically targets H3K14ac and works in synergy with RomA. Both effectors target host chromatin and bind the HBO1 histone acetyltransferase complex that acetylates H3K14. Full activity of RomA is dependent on the presence of LphD as H3K14 methylation levels are significantly decreased in a ∆lphD mutant. The dependency of these two chromatin-modifying effectors on each other is further substantiated by mutational and virulence assays revealing that the presence of only one of these two effectors impairs intracellular replication, while a double knockout (∆lphD∆romA) can restore intracellular replication. Uniquely, we present evidence for "para-effectors", an effector pair, that actively and coordinately modify host histones to hijack the host response. The identification of epigenetic marks modulated by pathogens has the potential to lead to the development of innovative therapeutic strategies to counteract bacterial infection and strengthening host defences.
Insights
Legionella pneumophila uses two secreted "para-effectors," LphD and RomA, to modify host histone H3K14 acetylation and methylation, coordinating epigenetic changes to enhance bacterial infection.
Area of Science:
- Microbiology and Epigenetics
- Bacterial Pathogenesis
- Host-Pathogen Interactions
Background:
- Legionella pneumophila (L. pneumophila) is an intracellular bacterium that manipulates host cells for replication.
- L. pneumophila secretes effector proteins, including RomA (a methyltransferase), to modify host proteins.
- Histone H3 lysine 14 (H3K14) is typically acetylated, but its methylation by L. pneumophila effectors was previously unknown.
Purpose of the Study:
- To elucidate the mechanism by which L. pneumophila induces H3K14 methylation.
- To investigate the role of L. pneumophila secreted factors in modifying host chromatin.
- To understand the synergistic action of L. pneumophila effectors in manipulating host epigenetic marks.
Main Methods:
- Identification and characterization of a novel L. pneumophila effector, LphD, a histone deacetylase.
- Analysis of histone modifications (H3K14 acetylation and methylation) in infected host cells.
- Mutational analysis of LphD and RomA, including virulence and intracellular replication assays.
Main Results:
- L. pneumophila secretes LphD, a histone deacetylase targeting H3K14ac, which acts synergistically with RomA.
- Both LphD and RomA target host chromatin and interact with the HBO1 histone acetyltransferase complex.
- Full H3K14 methylation activity by RomA is dependent on LphD; single effector mutants impair replication, while double mutants restore it.
Conclusions:
- L. pneumophila employs a unique 'para-effector' pair (LphD and RomA) to coordinately modify host H3K14.
- This coordinated epigenetic modification hijacks host responses, facilitating bacterial intracellular replication.
- Targeting pathogen-modulated epigenetic marks offers potential for novel therapeutic strategies against bacterial infections.
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