Targeting host epigenetic machinery: TheListeriaparadigm

Abstract

By modifying the host cell transcription programme, pathogenic bacteria disrupt a wide range of cellular processes and take control of the host's immune system. Conversely, by mobilising a network of defence genes, the host cells trigger various responses that allow them to tolerate or eliminate invaders. The study of the molecular basis of this crosstalk is crucial to the understanding of infectious diseases. Although research has long focused on the targeting of eukaryotic DNA‐binding transcription factors, more recently, another powerful way by which bacteria modify the expression of host genes has emerged: chromatin modifications in the cell nucleus. One of the most prolific bacterial models in this area has been Listeria monocytogenes, a facultative intracellular bacterium responsible for serious food‐borne infections. Here, we aim to highlight the contribution of this model to the field of bacteria‐mediated chromatin modifications. We will first recall the general principles of epigenetic regulation and then illustrate five mechanisms that mobilise the epigenetic machinery in response to Listeria factors, either through bacterial molecular patterns, a toxin, an invasion protein, or nucleomodulins. Strategies used by Listeria to control the expression of host genes at the chromatin level, by activation of cytosolic signalling pathways or direct targeting of epifactors in the nucleus, have contributed to the emergence of a new discipline combining cellular microbiology and epigenetics: “patho‐epigenetics.”

Trained immunity and host‐pathogen interactions

“…Numerous bacterial proteins have the ability to induce host epigenetic modifications. These include the lethal toxin of Bacillus anthracis , perfringolysin O from Clostridium perfringens , aerolysin from Aeromonas hydrophila , pneumolysin of S. pneumoniae and listeriolysin O from L. monocytogenes that mediate histone dephosphorylation and deacetylation through pore formation, resulting in impaired cytokine production and immune cell recruitment (Bierne & Hamon, 2020; Hamon et al, 2007; Raymond et al, 2009). Some bacterial factors also act by directly targeting host factors involved in epigenetic remodelling.…”

Histone H3 deacetylation promotes host cell viability for efficient infection byListeria monocytogenes

“…Over the last decade, host nuclear factors and processes have been identified as common targets for bacterial pathogen manipulation during infection (Bierne & Hamon, 2020;Eldridge et al, 2020a;Dong & Hamon, 2020). Previous work demonstrated that, through InlB-induced signalling, L. monocytogenes triggers dephosphorylation of SIRT2 and co-opts its activity resulting in H3K18 deacetylation and augmented infection.…”

Bacterial Factors Targeting the Nucleus: The Growing Family of Nucleomodulins

“…This Gram-positive bacterium invades many cell types and affects various organs such as the liver, spleen, placenta, and brain. Studies on Listeria have been particularly useful in identifying various mechanisms of host-pathogen interaction [19,20], in particular, chromatin changes induced by bacteria [12,21]. One of these mechanisms involves a virulence protein secreted by the general Sec secretion system, Listeria nuclear targeted protein A (LntA), the first protein of this pathogen detected in the nucleus [8].…”

“…Nucleomodulins are also promising tools for understanding the biology of the nucleus. For example, the study of Listeria nucleomodulin LntA has led to the characterization of BAHD1 as a new epigenetic regulator [21]. The study of nucleomodulin target genes could also lead to the discovery of new pathways involved in infectious diseases and potential targets for pharmacological intervention.…”