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H. Bierne
Université Paris-Saclay, INRAE, AgroParisTech, MIcalis Institute

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Protocol
Published: 26 September 2020 in Methods in Molecular Biology
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The pathogen Listeria monocytogenes is a facultative intracellular bacterium, which targets a large range of cell types. Following entry, bacteria disrupt the invasion vacuole and reach the cytoplasm where they replicate and use the actin cytoskeleton to propel themselves from cell to cell. Mammalian epithelial cells grown in vitro can be used to study the different steps of the intracellular life of Listeria. However, rapid multiplication and dissemination of bacteria can induce important cell death and detachment, resulting in the formation of lytic plaques. Thus, in vitro infections with L. monocytogenes are usually restricted to short time courses, from a few minutes to one day. Here, we present a method to study long-term L. monocytogenes infections in epithelial cells using epifluorescence microscopy. This protocol enables the observation of actin-based motility, intercellular dissemination foci, and entrapment of L. monocytogenes within vacuoles of persistence termed “Listeria-Containing Vacuoles” (LisCVs). We also describe a protocol to study the recruitment of cytoskeletal proteins at Listeria actin comet tails, as well as a method to assess the membrane integrity of intracellular bacteria using a LIVE/DEAD viability assay.

ACS Style

Hélène Bierne; Mounia Kortebi; Natalie Descoeudres. Microscopy of Intracellular Listeria monocytogenes in Epithelial Cells. Methods in Molecular Biology 2020, 201 -215.

AMA Style

Hélène Bierne, Mounia Kortebi, Natalie Descoeudres. Microscopy of Intracellular Listeria monocytogenes in Epithelial Cells. Methods in Molecular Biology. 2020; ():201-215.

Chicago/Turabian Style

Hélène Bierne; Mounia Kortebi; Natalie Descoeudres. 2020. "Microscopy of Intracellular Listeria monocytogenes in Epithelial Cells." Methods in Molecular Biology , no. : 201-215.

Research article
Published: 14 May 2020 in PLOS ONE
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BAHD1 is a heterochomatinization factor recently described as a component of a multiprotein complex associated with histone deacetylases HDAC1/2. The physiological and patho-physiological functions of BAHD1 are not yet well characterized. Here, we examined the consequences of BAHD1 deficiency in the brains of male mice. While Bahd1 knockout mice had no detectable defects in brain anatomy, RNA sequencing profiling revealed about 2500 deregulated genes in Bahd1-/- brains compared to Bahd1+/+ brains. A majority of these genes were involved in nervous system development and function, behavior, metabolism and immunity. Exploration of the Allen Brain Atlas and Dropviz databases, assessing gene expression in the brain, revealed that expression of the Bahd1 gene was limited to a few territories and cell subtypes, particularly in the hippocampal formation, the isocortex and the olfactory regions. The effect of partial BAHD1 deficiency on behavior was then evaluated on Bahd1 heterozygous male mice, which have no lethal or metabolic phenotypes. Bahd1+/- mice showed anxiety-like behavior and reduced prepulse inhibition (PPI) of the startle response. Altogether, these results suggest that BAHD1 plays a role in chromatin-dependent gene regulation in a subset of brain cells and support recent evidence linking genetic alteration of BAHD1 to psychiatric disorders in a human patient.

ACS Style

Renaud Pourpre; Laurent Naudon; Hamid Meziane; Goran Lakisic; Luc Jouneau; Hugo Varet; Rachel Legendre; Olivia Wendling; Mohammed Selloum; Caroline Proux; Jean-Yves Coppée; Yann Herault; Hélène Bierne. BAHD1 haploinsufficiency results in anxiety-like phenotypes in male mice. PLOS ONE 2020, 15, e0232789 .

AMA Style

Renaud Pourpre, Laurent Naudon, Hamid Meziane, Goran Lakisic, Luc Jouneau, Hugo Varet, Rachel Legendre, Olivia Wendling, Mohammed Selloum, Caroline Proux, Jean-Yves Coppée, Yann Herault, Hélène Bierne. BAHD1 haploinsufficiency results in anxiety-like phenotypes in male mice. PLOS ONE. 2020; 15 (5):e0232789.

Chicago/Turabian Style

Renaud Pourpre; Laurent Naudon; Hamid Meziane; Goran Lakisic; Luc Jouneau; Hugo Varet; Rachel Legendre; Olivia Wendling; Mohammed Selloum; Caroline Proux; Jean-Yves Coppée; Yann Herault; Hélène Bierne. 2020. "BAHD1 haploinsufficiency results in anxiety-like phenotypes in male mice." PLOS ONE 15, no. 5: e0232789.

Review
Published: 31 March 2020 in Toxins
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Pathogenic bacteria secrete a variety of proteins that manipulate host cell function by targeting components of the plasma membrane, cytosol, or organelles. In the last decade, several studies identified bacterial factors acting within the nucleus on gene expression or other nuclear processes, which has led to the emergence of a new family of effectors called “nucleomodulins”. In human and animal pathogens, Listeria monocytogenes for Gram-positive bacteria and Anaplasma phagocytophilum, Ehrlichia chaffeensis, Chlamydia trachomatis, Legionella pneumophila, Shigella flexneri, and Escherichia coli for Gram-negative bacteria, have led to pioneering discoveries. In this review, we present these paradigms and detail various mechanisms and core elements (e.g., DNA, histones, epigenetic regulators, transcription or splicing factors, signaling proteins) targeted by nucleomodulins. We particularly focus on nucleomodulins interacting with epifactors, such as LntA of Listeria and ankyrin repeat- or tandem repeat-containing effectors of Rickettsiales, and nucleomodulins from various bacterial species acting as post-translational modification enzymes. The study of bacterial nucleomodulins not only generates important knowledge about the control of host responses by microbes but also creates new tools to decipher the dynamic regulations that occur in the nucleus. This research also has potential applications in the field of biotechnology. Finally, this raises questions about the epigenetic effects of infectious diseases.

ACS Style

Hélène Bierne; Renaud Pourpre. Bacterial Factors Targeting the Nucleus: The Growing Family of Nucleomodulins. Toxins 2020, 12, 220 .

AMA Style

Hélène Bierne, Renaud Pourpre. Bacterial Factors Targeting the Nucleus: The Growing Family of Nucleomodulins. Toxins. 2020; 12 (4):220.

Chicago/Turabian Style

Hélène Bierne; Renaud Pourpre. 2020. "Bacterial Factors Targeting the Nucleus: The Growing Family of Nucleomodulins." Toxins 12, no. 4: 220.

Review
Published: 17 March 2020 in Cellular Microbiology
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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.”

ACS Style

Hélène Bierne; Mélanie Hamon. Targeting host epigenetic machinery: The Listeria paradigm. Cellular Microbiology 2020, 22, 1 .

AMA Style

Hélène Bierne, Mélanie Hamon. Targeting host epigenetic machinery: The Listeria paradigm. Cellular Microbiology. 2020; 22 (4):1.

Chicago/Turabian Style

Hélène Bierne; Mélanie Hamon. 2020. "Targeting host epigenetic machinery: The Listeria paradigm." Cellular Microbiology 22, no. 4: 1.

Mini review article
Published: 15 May 2018 in Frontiers in Cellular and Infection Microbiology
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Intracellular bacterial pathogens are generally classified into two types: those that exploit host membrane trafficking to construct specific niches in vacuoles (i.e., “vacuolar pathogens”), and those that escape from vacuoles into the cytosol, where they proliferate and often spread to neighboring cells (i.e., “cytosolic pathogens”). However, the boundary between these distinct intracellular phenotypes is tenuous and may depend on the timing of infection and on the host cell type. Here, we discuss recent progress highlighting this phenotypic duality in Listeria monocytogenes, which has long been a model for cytosolic pathogens, but now emerges as a bacterium also capable of residing in vacuoles, in a slow/non-growing state. The ability of L. monocytogenes to enter a persistence stage in vacuoles might play a role during the asymptomatic incubation period of listeriosis and/or the carriage of this pathogen in asymptomatic hosts. Moreover, persistent vacuolar Listeria could be less susceptible to antibiotics and more difficult to detect by routine techniques of clinical biology. These hypotheses deserve to be explored in order to better manage the risks related to this food-borne pathogen.

ACS Style

Hélène Bierne; Eliane Milohanic; Mounia Kortebi. To Be Cytosolic or Vacuolar: The Double Life of Listeria monocytogenes. Frontiers in Cellular and Infection Microbiology 2018, 8, 136 .

AMA Style

Hélène Bierne, Eliane Milohanic, Mounia Kortebi. To Be Cytosolic or Vacuolar: The Double Life of Listeria monocytogenes. Frontiers in Cellular and Infection Microbiology. 2018; 8 ():136.

Chicago/Turabian Style

Hélène Bierne; Eliane Milohanic; Mounia Kortebi. 2018. "To Be Cytosolic or Vacuolar: The Double Life of Listeria monocytogenes." Frontiers in Cellular and Infection Microbiology 8, no. : 136.

Research article
Published: 30 November 2017 in PLOS Pathogens
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Listeria monocytogenes causes listeriosis, a foodborne disease that poses serious risks to fetuses, newborns and immunocompromised adults. This intracellular bacterial pathogen proliferates in the host cytosol and exploits the host actin polymerization machinery to spread from cell-to-cell and disseminate in the host. Here, we report that during several days of infection in human hepatocytes or trophoblast cells, L. monocytogenes switches from this active motile lifestyle to a stage of persistence in vacuoles. Upon intercellular spread, bacteria gradually stopped producing the actin-nucleating protein ActA and became trapped in lysosome-like vacuoles termed Listeria-Containing Vacuoles (LisCVs). Subpopulations of bacteria resisted degradation in LisCVs and entered a slow/non-replicative state. During the subculture of host cells harboring LisCVs, bacteria showed a capacity to cycle between the vacuolar and the actin-based motility stages. When ActA was absent, such as in ΔactA mutants, vacuolar bacteria parasitized host cells in the so-called “viable but non-culturable” state (VBNC), preventing their detection by conventional colony counting methods. The exposure of infected cells to high doses of gentamicin did not trigger the formation of LisCVs, but selected for vacuolar and VBNC bacteria. Together, these results reveal the ability of L. monocytogenes to enter a persistent state in a subset of epithelial cells, which may favor the asymptomatic carriage of this pathogen, lengthen the incubation period of listeriosis, and promote bacterial survival during antibiotic therapy. L. monocytogenes is a model intracellular pathogen that replicates in the cytoplasm of mammalian cells and disseminate in the host using actin-based motility. Here, we reveal that L. monocytogenes changes its lifestyle and persists in lysosomal vacuoles during long-term infection of human hepatocytes and trophoblast cells. When the virulence factor ActA is not expressed, subpopulations of vacuolar bacteria enter a dormant viable but non-culturable (VBNC) state. This novel facet of the L. monocytogenes intracellular life could contribute to the asymptomatic carriage of this pathogen in epithelial tissues and render it tolerant to antibiotic therapy and undetectable by routine culture techniques.

ACS Style

Mounia Kortebi; Eliane Milohanic; Gabriel Mitchell; Christine Péchoux; Marie-Christine Prevost; Pascale Cossart; Hélène Bierne. Listeria monocytogenes switches from dissemination to persistence by adopting a vacuolar lifestyle in epithelial cells. PLOS Pathogens 2017, 13, e1006734 .

AMA Style

Mounia Kortebi, Eliane Milohanic, Gabriel Mitchell, Christine Péchoux, Marie-Christine Prevost, Pascale Cossart, Hélène Bierne. Listeria monocytogenes switches from dissemination to persistence by adopting a vacuolar lifestyle in epithelial cells. PLOS Pathogens. 2017; 13 (11):e1006734.

Chicago/Turabian Style

Mounia Kortebi; Eliane Milohanic; Gabriel Mitchell; Christine Péchoux; Marie-Christine Prevost; Pascale Cossart; Hélène Bierne. 2017. "Listeria monocytogenes switches from dissemination to persistence by adopting a vacuolar lifestyle in epithelial cells." PLOS Pathogens 13, no. 11: e1006734.

Editorial
Published: 16 August 2017 in Virulence
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ACS Style

Hélène Bierne; Christina Nielsen-Leroux. Is there a transgenerational inheritance of host resistance against pathogens? Lessons from the Galleria mellonella-Bacillus thuringiensis interaction model. Virulence 2017, 8, 1471 -1474.

AMA Style

Hélène Bierne, Christina Nielsen-Leroux. Is there a transgenerational inheritance of host resistance against pathogens? Lessons from the Galleria mellonella-Bacillus thuringiensis interaction model. Virulence. 2017; 8 (8):1471-1474.

Chicago/Turabian Style

Hélène Bierne; Christina Nielsen-Leroux. 2017. "Is there a transgenerational inheritance of host resistance against pathogens? Lessons from the Galleria mellonella-Bacillus thuringiensis interaction model." Virulence 8, no. 8: 1471-1474.

Book chapter
Published: 27 May 2017 in Epigenetics and Neuroendocrinology
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Multidisciplinary approaches combining microbiology, cell biology, and genetics have improved our understanding of bacterial diseases by elucidating mechanisms employed by bacteria to manipulate eukaryotic cellular processes. In parallel, research on epigenetics has increased our knowledge about eukaryotic gene expression by providing a mechanistic basis for the amazing plasticity of the genome in response to developmental and environmental cues. These two fields of research have now converged, providing information about the ways in which bacteria shape the epigenome and the mechanisms by which the epigenetic machinery allows the host to respond to colonization by pathogenic or commensal bacteria. The study of this cross talk has revealed remarkable diversity in the mechanisms of action of bacteria on chromatin and has identified epigenetic regulators involved in host responsiveness to bacteria. One powerful strategy used by intracellular pathogens (e.g., Anaplasma, Chlamydia, Ehrlichia, Legionella, Listeria, Mycobacteria, Mycoplasma, Shigella) is the secretion of nucleomodulins that manipulate chromatin structure in the host nucleus. The effects of this dialog are often limited in time, causing transient gene expression changes. However, increasing evidence suggests that certain epigenetic changes triggered by bacterial molecules are long-lasting, leading to the priming of transcriptional responses and the reprogramming of genes involved in inflammation or tolerance, with consequences for reinfection and polymicrobial infections. In addition, the effects of bacteria on the host epigenome may ultimately modify the identity of the cell by breaking epigenetic barriers, leading to cell differentiation, dedifferentiation, or trans-differentiation, thereby potentially contributing to tissue remodeling and emergence of complex diseases.

ACS Style

Hélène Bierne. Cross Talk Between Bacteria and the Host Epigenetic Machinery. Epigenetics and Neuroendocrinology 2017, 113 -158.

AMA Style

Hélène Bierne. Cross Talk Between Bacteria and the Host Epigenetic Machinery. Epigenetics and Neuroendocrinology. 2017; ():113-158.

Chicago/Turabian Style

Hélène Bierne. 2017. "Cross Talk Between Bacteria and the Host Epigenetic Machinery." Epigenetics and Neuroendocrinology , no. : 113-158.

Review
Published: 05 March 2016 in Current Topics in Microbiology and Immunology
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Bacterial surface proteins constitute an amazing repertoire of molecules with important functions such as adherence, invasion, signalling and interaction with the host immune system or environment. In Gram-positive bacteria, many surface proteins of the "LPxTG" family are anchored to the peptidoglycan (PG) by an enzyme named sortase. While this anchoring mechanism has been clearly deciphered, less is known about the spatial organization of cell wall-anchored proteins in the bacterial envelope. Here, we review the question of the precise spatial and temporal positioning of LPxTG proteins in subcellular domains in spherical and ellipsoid bacteria (Staphylococcus aureus, Streptococcus pyogenes, Streptococcus agalactiae and Enterococcus faecalis) and in the rod-shaped bacterium Listeria monocytogenes. Deposition at specific sites of the cell wall is a dynamic process tightly connected to cell division, secretion, cell morphogenesis and levels of gene expression. Studying spatial occupancy of these cell wall-anchored proteins not only provides information on PG dynamics in responses to environmental changes, but also suggests that pathogenic bacteria control the distribution of virulence factors at specific sites of the surface, including pole, septa or lateral sites, during the infectious process.

ACS Style

Shaynoor Dramsi; Hélène Bierne. Spatial Organization of Cell Wall-Anchored Proteins at the Surface of Gram-Positive Bacteria. Current Topics in Microbiology and Immunology 2016, 177 -201.

AMA Style

Shaynoor Dramsi, Hélène Bierne. Spatial Organization of Cell Wall-Anchored Proteins at the Surface of Gram-Positive Bacteria. Current Topics in Microbiology and Immunology. 2016; ():177-201.

Chicago/Turabian Style

Shaynoor Dramsi; Hélène Bierne. 2016. "Spatial Organization of Cell Wall-Anchored Proteins at the Surface of Gram-Positive Bacteria." Current Topics in Microbiology and Immunology , no. : 177-201.

Research article
Published: 03 March 2016 in PLOS Genetics
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BAHD1 is a vertebrate protein that promotes heterochromatin formation and gene repression in association with several epigenetic regulators. However, its physiological roles remain unknown. Here, we demonstrate that ablation of the Bahd1 gene results in hypocholesterolemia, hypoglycemia and decreased body fat in mice. It also causes placental growth restriction with a drop of trophoblast glycogen cells, a reduction of fetal weight and a high neonatal mortality rate. By intersecting transcriptome data from murine Bahd1 knockout (KO) placentas at stages E16.5 and E18.5 of gestation, Bahd1-KO embryonic fibroblasts, and human cells stably expressing BAHD1, we also show that changes in BAHD1 levels alter expression of steroid/lipid metabolism genes. Biochemical analysis of the BAHD1-associated multiprotein complex identifies MIER proteins as novel partners of BAHD1 and suggests that BAHD1-MIER interaction forms a hub for histone deacetylases and methyltransferases, chromatin readers and transcription factors. We further show that overexpression of BAHD1 leads to an increase of MIER1 enrichment on the inactive X chromosome (Xi). In addition, BAHD1 and MIER1/3 repress expression of the steroid hormone receptor genes ESR1 and PGR, both playing important roles in placental development and energy metabolism. Moreover, modulation of BAHD1 expression in HEK293 cells triggers epigenetic changes at the ESR1 locus. Together, these results identify BAHD1 as a core component of a chromatin-repressive complex regulating placental morphogenesis and body fat storage and suggest that its dysfunction may contribute to several human diseases.

ACS Style

Goran Lakisic; Alice Lebreton; Renaud Pourpre; Olivia Wendling; Emanuele Libertini; Elizabeth Radford; Morwenna Le Guillou; Marie-France Champy; Marie Wattenhofer-Donzé; Guillaume Soubigou; Slimane Ait-Si-Ali; Jean Feunteun; Tania Sorg; Jean-Yves Coppée; Anne C. Ferguson-Smith; Pascale Cossart; Hélène Bierne. Role of the BAHD1 Chromatin-Repressive Complex in Placental Development and Regulation of Steroid Metabolism. PLOS Genetics 2016, 12, e1005898 .

AMA Style

Goran Lakisic, Alice Lebreton, Renaud Pourpre, Olivia Wendling, Emanuele Libertini, Elizabeth Radford, Morwenna Le Guillou, Marie-France Champy, Marie Wattenhofer-Donzé, Guillaume Soubigou, Slimane Ait-Si-Ali, Jean Feunteun, Tania Sorg, Jean-Yves Coppée, Anne C. Ferguson-Smith, Pascale Cossart, Hélène Bierne. Role of the BAHD1 Chromatin-Repressive Complex in Placental Development and Regulation of Steroid Metabolism. PLOS Genetics. 2016; 12 (3):e1005898.

Chicago/Turabian Style

Goran Lakisic; Alice Lebreton; Renaud Pourpre; Olivia Wendling; Emanuele Libertini; Elizabeth Radford; Morwenna Le Guillou; Marie-France Champy; Marie Wattenhofer-Donzé; Guillaume Soubigou; Slimane Ait-Si-Ali; Jean Feunteun; Tania Sorg; Jean-Yves Coppée; Anne C. Ferguson-Smith; Pascale Cossart; Hélène Bierne. 2016. "Role of the BAHD1 Chromatin-Repressive Complex in Placental Development and Regulation of Steroid Metabolism." PLOS Genetics 12, no. 3: e1005898.

Original research article
Published: 01 December 2015 in Frontiers in Genetics
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BAH domain-containing protein 1 (BAHD1) is involved in heterochromatin formation and gene repression in human cells. BAHD1 also localizes to the inactive X chromosome (Xi), but the functional significance of this targeting is unknown. So far, research on this protein has been hampered by its low endogenous abundance and its role in epigenetic regulation remains poorly explored. In this work, we used whole-genome bisulfite sequencing (BS-seq) to compare the DNA methylation profile of HEK293 cells expressing low levels of BAHD1 (HEK-CT) to that of isogenic cells stably overexpressing BAHD1 (HEK-BAHD1). We show that increasing BAHD1 levels induces de novo DNA methylation on autosomes and a marked hypomethylation on the X chromosome (chrX). We identified 91,358 regions that have different methylation patterns in HEK-BAHD1 compared to HEK-CT cells (termed “BAHD1-DMRs”), of which 83,850 mapped on autosomes and 7508 on the X chromosome (chrX). Autosomal BAHD1-DMRs were predominantly hypermethylated and located to satellites, interspersed repeats, and intergenic regions. In contrast, BAHD1-DMRs on chrX were mainly hypomethylated and located to gene bodies and enhancers. We further found that BAHD1-DMRs display a higher-order organization by being clustered within large chromosomal domains. Half of these “BAHD1-Associated differentially methylated Domains” (BADs) overlapped with lamina-associated domains (LADs). Based on these results, we propose that BAHD1-mediated heterochromatin formation is linked to DNA methylation and may play a role in the spatial architecture of the genome.

ACS Style

Emanuele Libertini; Alice Lebreton; Goran Lakisic; Marie-Agnès Dillies; Stephan Beck; Jean-Yves Coppée; Pascale Cossart; Hélène Bierne. Overexpression of the Heterochromatinization Factor BAHD1 in HEK293 Cells Differentially Reshapes the DNA Methylome on Autosomes and X Chromosome. Frontiers in Genetics 2015, 6, 1 .

AMA Style

Emanuele Libertini, Alice Lebreton, Goran Lakisic, Marie-Agnès Dillies, Stephan Beck, Jean-Yves Coppée, Pascale Cossart, Hélène Bierne. Overexpression of the Heterochromatinization Factor BAHD1 in HEK293 Cells Differentially Reshapes the DNA Methylome on Autosomes and X Chromosome. Frontiers in Genetics. 2015; 6 ():1.

Chicago/Turabian Style

Emanuele Libertini; Alice Lebreton; Goran Lakisic; Marie-Agnès Dillies; Stephan Beck; Jean-Yves Coppée; Pascale Cossart; Hélène Bierne. 2015. "Overexpression of the Heterochromatinization Factor BAHD1 in HEK293 Cells Differentially Reshapes the DNA Methylome on Autosomes and X Chromosome." Frontiers in Genetics 6, no. : 1.

Journal article
Published: 11 August 2015 in eLife
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ISG15 is an interferon-stimulated, linear di-ubiquitin-like protein, with anti-viral activity. The role of ISG15 during bacterial infection remains elusive. We show that ISG15 expression in nonphagocytic cells is dramatically induced upon Listeria infection. Surprisingly this induction can be type I interferon independent and depends on the cytosolic surveillance pathway, which senses bacterial DNA and signals through STING, TBK1, IRF3 and IRF7. Most importantly, we observed that ISG15 expression restricts Listeria infection in vitro and in vivo. We made use of stable isotope labeling in tissue culture (SILAC) to identify ISGylated proteins that could be responsible for the protective effect. Strikingly, infection or overexpression of ISG15 leads to ISGylation of ER and Golgi proteins, which correlates with increased secretion of cytokines known to counteract infection. Together, our data reveal a previously uncharacterized ISG15-dependent restriction of Listeria infection, reinforcing the view that ISG15 is a key component of the innate immune response.

ACS Style

Lilliana Radoshevich; Francis Impens; David Ribet; Juan J Quereda; To Nam Tham; Marie-Anne Nahori; Helene Bierne; Olivier Dussurget; Javier Pizarro-Cerdá; Klaus-Peter Knobeloch; Pascale Cossart. ISG15 counteracts Listeria monocytogenes infection. eLife 2015, 4, e06848 .

AMA Style

Lilliana Radoshevich, Francis Impens, David Ribet, Juan J Quereda, To Nam Tham, Marie-Anne Nahori, Helene Bierne, Olivier Dussurget, Javier Pizarro-Cerdá, Klaus-Peter Knobeloch, Pascale Cossart. ISG15 counteracts Listeria monocytogenes infection. eLife. 2015; 4 ():e06848.

Chicago/Turabian Style

Lilliana Radoshevich; Francis Impens; David Ribet; Juan J Quereda; To Nam Tham; Marie-Anne Nahori; Helene Bierne; Olivier Dussurget; Javier Pizarro-Cerdá; Klaus-Peter Knobeloch; Pascale Cossart. 2015. "ISG15 counteracts Listeria monocytogenes infection." eLife 4, no. : e06848.

Journal article
Published: 22 June 2014 in Nature Immunology
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Type III interferons have important antiviral functions, but they are poorly described compared to type I interferons. Kagan and colleagues demonstrate that type III interferons are induced on peroxisomes in response to a variety of viral triggers. Type I interferon responses are considered the primary means by which viral infections are controlled in mammals. Despite this view, several pathogens activate antiviral responses in the absence of type I interferons. The mechanisms controlling type I interferon–independent responses are undefined. We found that RIG-I like receptors (RLRs) induce type III interferon expression in a variety of human cell types, and identified factors that differentially regulate expression of type I and type III interferons. We identified peroxisomes as a primary site of initiation of type III interferon expression, and revealed that the process of intestinal epithelial cell differentiation upregulates peroxisome biogenesis and promotes robust type III interferon responses in human cells. These findings highlight the importance of different intracellular organelles in specific innate immune responses.

ACS Style

Charlotte Odendall; Evelyn Dixit; Fabrizia Stavru; Helene Bierne; Kate M. Franz; Ann Durbin; Steeve Boulant; Lee Gehrke; Pascale Cossart; Jonathan C. Kagan. Diverse intracellular pathogens activate type III interferon expression from peroxisomes. Nature Immunology 2014, 15, 717 -726.

AMA Style

Charlotte Odendall, Evelyn Dixit, Fabrizia Stavru, Helene Bierne, Kate M. Franz, Ann Durbin, Steeve Boulant, Lee Gehrke, Pascale Cossart, Jonathan C. Kagan. Diverse intracellular pathogens activate type III interferon expression from peroxisomes. Nature Immunology. 2014; 15 (8):717-726.

Chicago/Turabian Style

Charlotte Odendall; Evelyn Dixit; Fabrizia Stavru; Helene Bierne; Kate M. Franz; Ann Durbin; Steeve Boulant; Lee Gehrke; Pascale Cossart; Jonathan C. Kagan. 2014. "Diverse intracellular pathogens activate type III interferon expression from peroxisomes." Nature Immunology 15, no. 8: 717-726.

Journal article
Published: 29 May 2014 in The FEBS Journal
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Ral proteins are small GTPases that play critical roles in normal physiology and in oncogenesis. There is little information on the GTPase-activating proteins (GAPs) that downregulate their activity. Here, we provide evidence that the noncatalytic β subunit of RalGAPα1/2 β complexes is involved in mitotic control. RalGAPβ localizes to the Golgi and nucleus during interphase, and relocalizes to the mitotic spindle and cytokinetic intercellular bridge during mitosis. Depletion of RalGAPβ causes chromosome misalignment and decreases the amount of mitotic cyclin B1, disturbing the metaphase-to-anaphase transition. Overexpression of RalGAPβ interferes with cell division, leading to binucleation and multinucleation, and cell death. We propose that RalGAPβ plays an essential role in the sequential progression of mitosis by controlling the spatial and temporal activation of Ral GTPases in the spindle assembly checkpoint (SAC) and cytokinesis. Deregulation of RalGAPβ might cause genomic instability, leading to human carcinogenesis.

ACS Style

Nicolas Personnic; Goran Lakisic; Edith Gouin; Alix Rousseau; Alexis Gautreau; Pascale Cossart; Hélène Bierne. A role for Ral GTPase-activating protein subunit β in mitotic regulation. The FEBS Journal 2014, 281, 2977 -2989.

AMA Style

Nicolas Personnic, Goran Lakisic, Edith Gouin, Alix Rousseau, Alexis Gautreau, Pascale Cossart, Hélène Bierne. A role for Ral GTPase-activating protein subunit β in mitotic regulation. The FEBS Journal. 2014; 281 (13):2977-2989.

Chicago/Turabian Style

Nicolas Personnic; Goran Lakisic; Edith Gouin; Alix Rousseau; Alexis Gautreau; Pascale Cossart; Hélène Bierne. 2014. "A role for Ral GTPase-activating protein subunit β in mitotic regulation." The FEBS Journal 281, no. 13: 2977-2989.

Comparative study
Published: 01 May 2014 in mBio
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For nearly 3 decades, listeriologists and immunologists have used mainly three strains of the same serovar (1/2a) to analyze the virulence of the bacterial pathogen Listeria monocytogenes . The genomes of two of these strains, EGD-e and 10403S, were released in 2001 and 2008, respectively. Here we report the genome sequence of the third reference strain, EGD, and extensive genomic and phenotypic comparisons of the three strains. Strikingly, EGD-e is genetically highly distinct from EGD (29,016 single nucleotide polymorphisms [SNPs]) and 10403S (30,296 SNPs), and is more related to serovar 1/2c than 1/2a strains. We also found that while EGD and 10403S strains are genetically very close (317 SNPs), EGD has a point mutation in the transcriptional regulator PrfA (PrfA*), leading to constitutive expression of several major virulence genes. We generated an EGD-e PrfA* mutant and showed that EGD behaves like this strain in vitro , with slower growth in broth and higher invasiveness in human cells than those of EGD-e and 10403S. In contrast, bacterial counts in blood, liver, and spleen during infection in mice revealed that EGD and 10403S are less virulent than EGD-e, which is itself less virulent than EGD-e PrfA*. Thus, constitutive expression of PrfA-regulated virulence genes does not appear to provide a significant advantage to the EGD strain during infection in vivo , highlighting the fact that in vitro invasion assays are not sufficient for evaluating the pathogenic potential of L. monocytogenes strains. Together, our results pave the way for deciphering unexplained differences or discrepancies in experiments using different L. monocytogenes strains. IMPORTANCE Over the past 3 decades, Listeria has become a model organism for host-pathogen interactions, leading to critical discoveries in a broad range of fields, including bacterial gene regulation, cell biology, and bacterial pathophysiology. Scientists studying Listeria use primarily three pathogenic strains: EGD, EGD-e, and 10403S. Despite many studies on EGD, it is the only one of the three strains whose genome has not been sequenced. Here we report the sequence of its genome and a series of important genomic and phenotypic differences between the three strains, in particular, a critical mutation in EGD’s PrfA, the main regulator of Listeria virulence. Our results show that the three strains display differences which may play an important role in the virulence differences observed between the strains. Our findings will be of critical relevance to listeriologists and immunologists who have used or may use Listeria as a tool to study the pathophysiology of listeriosis and immune responses.

ACS Style

Christophe Bécavin; Christiane Bouchier; Pierre Lechat; Cristel Archambaud; Sophie Creno; Edith Gouin; Zongfu Wu; Andreas Kühbacher; Sylvain Brisse; M. Graciela Pucciarelli; Francisco García-Del Portillo; Torsten Hain; Daniel A. Portnoy; Trinad Chakraborty; Marc Lecuit; Javier Pizarro-Cerdá; Ivan Moszer; Helene Bierne; Pascale Cossart. Comparison of Widely Used Listeria monocytogenes Strains EGD, 10403S, and EGD-e Highlights Genomic Differences Underlying Variations in Pathogenicity. mBio 2014, 5, e00969-14 -14.

AMA Style

Christophe Bécavin, Christiane Bouchier, Pierre Lechat, Cristel Archambaud, Sophie Creno, Edith Gouin, Zongfu Wu, Andreas Kühbacher, Sylvain Brisse, M. Graciela Pucciarelli, Francisco García-Del Portillo, Torsten Hain, Daniel A. Portnoy, Trinad Chakraborty, Marc Lecuit, Javier Pizarro-Cerdá, Ivan Moszer, Helene Bierne, Pascale Cossart. Comparison of Widely Used Listeria monocytogenes Strains EGD, 10403S, and EGD-e Highlights Genomic Differences Underlying Variations in Pathogenicity. mBio. 2014; 5 (2):e00969-14-14.

Chicago/Turabian Style

Christophe Bécavin; Christiane Bouchier; Pierre Lechat; Cristel Archambaud; Sophie Creno; Edith Gouin; Zongfu Wu; Andreas Kühbacher; Sylvain Brisse; M. Graciela Pucciarelli; Francisco García-Del Portillo; Torsten Hain; Daniel A. Portnoy; Trinad Chakraborty; Marc Lecuit; Javier Pizarro-Cerdá; Ivan Moszer; Helene Bierne; Pascale Cossart. 2014. "Comparison of Widely Used Listeria monocytogenes Strains EGD, 10403S, and EGD-e Highlights Genomic Differences Underlying Variations in Pathogenicity." mBio 5, no. 2: e00969-14-14.

Review article
Published: 28 April 2014 in Frontiers in Cellular and Infection Microbiology
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Interferons (IFNs) are secreted proteins of the cytokine family that regulate innate and adaptive immune responses to infection. Although the importance of IFNs in the antiviral response has long been appreciated, their role in bacterial infections is more complex and is currently a major focus of investigation. This review summarizes our current knowledge of the role of these cytokines in host defense against the bacterial pathogen Listeria monocytogenes and highlights recent discoveries on the molecular mechanisms evolved by this intracellular bacterium to subvert IFN responses.

ACS Style

Olivier Dussurget; Helene Bierne; Pascale Cossart. The bacterial pathogen Listeria monocytogenes and the interferon family: type I, type II and type III interferons. Frontiers in Cellular and Infection Microbiology 2014, 4, 50 .

AMA Style

Olivier Dussurget, Helene Bierne, Pascale Cossart. The bacterial pathogen Listeria monocytogenes and the interferon family: type I, type II and type III interferons. Frontiers in Cellular and Infection Microbiology. 2014; 4 ():50.

Chicago/Turabian Style

Olivier Dussurget; Helene Bierne; Pascale Cossart. 2014. "The bacterial pathogen Listeria monocytogenes and the interferon family: type I, type II and type III interferons." Frontiers in Cellular and Infection Microbiology 4, no. : 50.

Journal article
Published: 28 February 2014 in mBio
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The nucleus has emerged as a key target for nucleomodulins, a family of effectors produced by bacterial pathogens to control host transcription or other nuclear processes. The virulence factor LntA from Listeria monocytogenes stimulates interferon responses during infection by inhibiting BAHD1, a nuclear protein involved in gene silencing by promoting heterochromatin formation. So far, whether the interaction between LntA and BAHD1 is direct and sufficient for inhibiting BAHD1 activity is unknown. Here, we functionally characterized the molecular interface between the two proteins in vitro and in transfected or infected human cells. Based on the known tridimensional structure of LntA, we identified a dilysine motif (K180/K181) in the elbow region of LntA and a central proline-rich region in BAHD1 as crucial for the direct LntA-BAHD1 interaction. To better understand the role played by the dilysine motif in the functionality of LntA, we solved the crystal structure of a K180D/K181D mutant to a 2.2-Å resolution. This mutant highlights a drastic redistribution of surface charges in the vicinity of a groove, which likely plays a role in nucleomodulin target recognition. Mutation of the strategic dilysine motif also abolished the recruitment of LntA to BAHD1-associated nuclear foci and impaired the LntA-mediated stimulation of interferon responses upon infection. Last, the strict conservation of residues K180 and K181 in LntA sequences from 188 L. monocytogenes strains of different serotypes and origins further supports their functional importance. Together, these results provide structural and functional details about the mechanism of inhibition of an epigenetic factor by a bacterial nucleomodulin. IMPORTANCE Pathogens have evolved various strategies to deregulate the expression of host defense genes during infection, such as targeting nuclear proteins. LntA, a secreted virulence factor from the bacterium Listeria monocytogenes , stimulates innate immune responses by inhibiting a chromatin-associated repressor, BAHD1. This study reveals the structural features of LntA required for BAHD1 inhibition. LntA interacts directly with a central domain of BAHD1 via a surface patch of conserved positive charges, located nearby a groove on the elbow region of LntA. By demonstrating that this patch is required for LntA function, we provide a better understanding of the molecular mechanism allowing a bacterial pathogen to control host chromatin compaction and gene expression.

ACS Style

Alice Lebreton; Viviana Job; Marie Ragon; Alban LE Monnier; Andréa Dessen; Pascale Cossart; Hélène Bierne. Structural Basis for the Inhibition of the Chromatin Repressor BAHD1 by the Bacterial Nucleomodulin LntA. mBio 2014, 5, e00775-13 -13.

AMA Style

Alice Lebreton, Viviana Job, Marie Ragon, Alban LE Monnier, Andréa Dessen, Pascale Cossart, Hélène Bierne. Structural Basis for the Inhibition of the Chromatin Repressor BAHD1 by the Bacterial Nucleomodulin LntA. mBio. 2014; 5 (1):e00775-13-13.

Chicago/Turabian Style

Alice Lebreton; Viviana Job; Marie Ragon; Alban LE Monnier; Andréa Dessen; Pascale Cossart; Hélène Bierne. 2014. "Structural Basis for the Inhibition of the Chromatin Repressor BAHD1 by the Bacterial Nucleomodulin LntA." mBio 5, no. 1: e00775-13-13.

Comment
Published: 16 July 2013 in EMBO reports
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Intracellular bacterial pathogens exploit the compartmentalization of the eukaryotic cell to create an environment that supports their own survival and growth. Among cellular organelles, the nucleus has long been considered to be mostly ‘safe’ from direct bacterial attacks. However, a growing number of molecules secreted by bacteria—termed ‘nucleomodulins’—target this central organelle to subvert the host defences of plants and animals [1]. The nucleus itself is a spatially organized compartment, with distinct chromosome territories and many non‐membrane‐delineated nuclear bodies. The most prominent of such subnuclear structures is the nucleolus, which is the site of both ribosomal RNA (rRNA) synthesis and the assembly of ribosomal subunits. In this issue of EMBO reports , new research by Ting Li, Feng Shao and colleagues shows that bacterial pathogens, such as Legionella and Burkholderia spp., can hijack the nucleolus by secreting SET‐domain effectors that target and modify rDNA chromatin (Fig 1; [2]). This activates rDNA transcription and promotes bacterial intracellular survival. SET‐related proteins exist in diverse bacterial species, which suggests that controlling rDNA transcription in the nucleolus might be a general virulence strategy. Figure 1. Bacterial histone methyltransferases control host gene expression in the nucleus and nucleolus. Legionella, Burkholderia and Chlamydia bacteria residing in cytosolic vacuoles secrete SET‐domain‐containing effector proteins in the cytosol through type 3 (T3SS; Burkholderia and Chlamydia ) or type 4 (T4SS; Legionella ) secretion systems. C. trachomatis secretes the nuclear effector (NUE), which targets the nucleus at unknown loci [4]. L. pneumophila secretes a methyltransferase (LpSET) that has been characterized in two ways: (i) in the nucleus, LpSET termed ‘RomA’ trimethylates histone H3 at Lys 14, causing a switch from acetylated to methylated H3K14 at specific gene promoters and thus transcriptional repression [9]; (ii) in the nucleolus, LpSET termed ‘LegAS4’ is proposed to bind to HP1 at …

ACS Style

Hélène Bierne. Nuclear microbiology—bacterial assault on the nucleolus. EMBO reports 2013, 14, 663 -664.

AMA Style

Hélène Bierne. Nuclear microbiology—bacterial assault on the nucleolus. EMBO reports. 2013; 14 (8):663-664.

Chicago/Turabian Style

Hélène Bierne. 2013. "Nuclear microbiology—bacterial assault on the nucleolus." EMBO reports 14, no. 8: 663-664.

Research article
Published: 30 May 2013 in PLOS Pathogens
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Listeria monocytogenes (Lm) is an invasive foodborne pathogen that leads to severe central nervous system and maternal-fetal infections. Lm ability to actively cross the intestinal barrier is one of its key pathogenic properties. Lm crosses the intestinal epithelium upon the interaction of its surface protein internalin (InlA) with its host receptor E-cadherin (Ecad). InlA-Ecad interaction is species-specific, does not occur in wild-type mice, but does in transgenic mice expressing human Ecad and knock-in mice expressing humanized mouse Ecad. To study listeriosis in wild-type mice, InlA has been “murinized” to interact with mouse Ecad. Here, we demonstrate that, unexpectedly, murinized InlA (InlAm) mediates not only Ecad-dependent internalization, but also N-cadherin-dependent internalization. Consequently, InlAm-expressing Lm targets not only goblet cells expressing luminally-accessible Ecad, as does Lm in humanized mice, but also targets villous M cells, which express luminally-accessible N-cadherin. This aberrant Lm portal of entry results in enhanced innate immune responses and intestinal barrier damage, both of which are not observed in wild-type Lm-infected humanized mice. Murinization of InlA therefore not only extends the host range of Lm, but also broadens its receptor repertoire, providing Lm with artifactual pathogenic properties. These results challenge the relevance of using InlAm-expressing Lm to study human listeriosis and in vivo host responses to this human pathogen. Co-evolution of microbes with their hosts can select stringently specific host-microbe interactions at the cell, tissue and species levels. Listeria monocytogenes (Lm) is a foodborne pathogen that causes a deadly systemic infection in humans. Lm crosses the intestinal epithelium upon the interaction of its surface protein InlA with E-cadherin (Ecad). InlA-Ecad interaction is species-specific, does not occur in wild-type mice, but does in transgenic mice expressing human Ecad and knock-in mice expressing humanized mouse Ecad. To study listeriosis in wild-type mice, InlA has been “murinized” to interact with mouse Ecad. Here, we demonstrate that in addition to interacting with mouse Ecad, InlAm also uses N-cadherin as a receptor, whereas InlA does not. This artifactual InlAm-N-cadherin interaction promotes bacterial translocation across villous M cells, a cell type which is not targeted by InlA-expressing bacteria. This leads to intestinal inflammation and intestinal barrier damage, both of which are not seen in humans and humanized mouse models permissive to InlA-Ecad interaction. These results challenge the relevance of using InlAm-expressing Lm as a model to study human listeriosis and host responses to this pathogen. They also illustrate that caution must be exercised before using “murinized” pathogens to study human infectious diseases.

ACS Style

Yu-Huan Tsai; Olivier Disson; Hélène Bierne; Marc Lecuit. Murinization of Internalin Extends Its Receptor Repertoire, Altering Listeria monocytogenes Cell Tropism and Host Responses. PLOS Pathogens 2013, 9, e1003381 .

AMA Style

Yu-Huan Tsai, Olivier Disson, Hélène Bierne, Marc Lecuit. Murinization of Internalin Extends Its Receptor Repertoire, Altering Listeria monocytogenes Cell Tropism and Host Responses. PLOS Pathogens. 2013; 9 (5):e1003381.

Chicago/Turabian Style

Yu-Huan Tsai; Olivier Disson; Hélène Bierne; Marc Lecuit. 2013. "Murinization of Internalin Extends Its Receptor Repertoire, Altering Listeria monocytogenes Cell Tropism and Host Responses." PLOS Pathogens 9, no. 5: e1003381.

Review
Published: 01 December 2012 in Cold Spring Harbor Perspectives in Medicine
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Epigenetic mechanisms regulate expression of the genome to generate various cell types during development or orchestrate cellular responses to external stimuli. Recent studies highlight that bacteria can affect the chromatin structure and transcriptional program of host cells by influencing diverse epigenetic factors (i.e., histone modifications, DNA methylation, chromatin-associated complexes, noncoding RNAs, and RNA splicing factors). In this article, we first review the molecular bases of the epigenetic language and then describe the current state of research regarding how bacteria can alter epigenetic marks and machineries. Bacterial-induced epigenetic deregulations may affect host cell function either to promote host defense or to allow pathogen persistence. Thus, pathogenic bacteria can be considered as potential epimutagens able to reshape the epigenome. Their effects might generate specific, long-lasting imprints on host cells, leading to a memory of infection that influences immunity and might be at the origin of unexplained diseases.

ACS Style

Hélène Bierne; Melanie Hamon; Pascale Cossart. Epigenetics and Bacterial Infections. Cold Spring Harbor Perspectives in Medicine 2012, 2, a010272 -a010272.

AMA Style

Hélène Bierne, Melanie Hamon, Pascale Cossart. Epigenetics and Bacterial Infections. Cold Spring Harbor Perspectives in Medicine. 2012; 2 (12):a010272-a010272.

Chicago/Turabian Style

Hélène Bierne; Melanie Hamon; Pascale Cossart. 2012. "Epigenetics and Bacterial Infections." Cold Spring Harbor Perspectives in Medicine 2, no. 12: a010272-a010272.