Epigenetics and Bacterial Infections

Institut Pasteur, Unité des Interactions Bactéries-Cellules, Paris F-75015, France.
Cold Spring Harbor Perspectives in Medicine (Impact Factor: 9.47). 12/2012; 2(12). DOI: 10.1101/cshperspect.a010272
Source: PubMed

ABSTRACT 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.

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Available from: Helene Bierne, May 11, 2014
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    • "Traditionally, the ability of bacterial-derived proteins to induce disruptions of cell signaling or major cellular processes such as NF-κB, MAPK, and JAK/STAT pathways, are the predominant focus of host–pathogen interaction studies (Brodsky and Medzhitov, 2009). Recently, there has been an increasing interest in the ability of these intracellular pathogens to direct alterations in host cell gene expression that promote survival and replication (Paschos and Allday, 2010; Bierne et al., 2012; Silmon de Monerri and Kim, 2014). It is now well recognized that bacterial pathogens can reprogram host gene expression either directly or indirectly, by altering the accessibility of gene promoters via epigenetic modifications. "
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    ABSTRACT: Obligate intracellular pathogenic bacteria evolved to manipulate their host cells with a limited range of proteins constrained by their compact genomes. The harsh environment of a phagocytic defense cell is one that challenges the majority of commensal and pathogenic bacteria; yet, these are the obligatory vertebrate homes for important pathogenic species in the Anaplasmataceae family. Survival requires that the parasite fundamentally alter the native functions of the cell to allow its entry, intracellular replication, and transmission to a hematophagous arthropod. The small genomic repertoires encode several eukaryotic-like proteins, including ankyrin A (AnkA) of Anaplasma phagocytophilum and Ank200 and tandem-repeat containing proteins of Ehrlichia chaffeensis that localize to the host cell nucleus and directly bind DNA. As a model, A. phagocytophilum AnkA appears to directly alter host cell gene expression by recruiting chromatin modifying enzymes such as histone deacetylases and methyltransferases or by acting directly on transcription in cis. While cis binding could feasibly alter limited ranges of genes and cellular functions, the complex and dramatic alterations in transcription observed with infection are difficult to explain on the basis of individually targeted genes. We hypothesize that nucleomodulins can act broadly, even genome-wide, to affect entire chromosomal neighborhoods and topologically associating chromatin domains by recruiting chromatin remodeling complexes or by altering the folding patterns of chromatin that bring distant regulatory regions together to coordinate control of transcriptional reprogramming. This review focuses on the A. phagocytophilum nucleomodulin AnkA, how it impacts host cell transcriptional responses, and current investigations that seek to determine how these multifunctional eukaryotic-like proteins facilitate epigenetic alterations and cellular reprogramming at the chromosomal level.
    Frontiers in Genetics 08/2014; 5:274. DOI:10.3389/fgene.2014.00274
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    • "The compounds in this collection are annotated as targeting pathways involved in the epigenetic regulation of chromatin (See Experimental procedures for details). Bacterial infection induced epigenetic changes such as histone modifications, DNA methylation, chromatin remodeling, which in turn affect host cell signaling has been shown to either promote host defense or increase susceptibility to infection [71]. To investigate Bp induced epigenetic changes which in turn may modulate MNGC formation, RAW264.7 macrophages were first pre-treated with the compound library and then infected with Bp K96243. "
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    ABSTRACT: Burkholderia pseudomallei (Bp), a Gram-negative, motile, facultative intracellular bacterium is the causative agent of melioidosis in humans and animals. The Bp genome encodes a repertoire of virulence factors, including the cluster 3 type III secretion system (T3SS-3), the cluster 1 type VI secretion system (T6SS-1), and the intracellular motility protein BimA, that enable the pathogen to invade both phagocytic and non-phagocytic cells. A unique hallmark of Bp infection both in vitro and in vivo is its ability to induce cell-to-cell fusion of macrophages to form multinucleated giant cells (MNGCs), which to date are semi-quantitatively reported following visual inspection. In this study we report the development of an automated high-content image acquisition and analysis assay to quantitate the Bp induced MNGC phenotype. Validation of the assay was performed using T6SS-1 ([increment]hcp1) and T3SS-3 ([increment]bsaZ) mutants of Bp that have been previously reported to exhibit defects in their ability to induce MNGCs. Finally, screening of a focused small molecule library identified several Histone Deacetylase (HDAC) inhibitors that inhibited Bp-induced MNGC formation of macrophages. We have successfully developed an automated HCI assay to quantitate MNGCs induced by Bp in macrophages. This assay was then used to characterize the phenotype of the Bp mutants for their ability to induce MNGC formation and identify small molecules that interfere with this process. Successful application of chemical genetics and functional reverse genetics siRNA approaches in the MNGC assay will help gain a better understanding of the molecular targets and cellular mechanisms responsible for the MNGC phenotype induced by Bp, by other bacteria such as Mycobacterium tuberculosis, or by exogenously added cytokines.
    BMC Microbiology 04/2014; 14(1):98. DOI:10.1186/1471-2180-14-98 · 2.73 Impact Factor
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    • "As sequencing on this scale improves with longer, better quality reads we will be able to perform de novo assemblies for each genome, which would allow all DNA in an isolate to be identified and tested for association with a specific trait. It has been suggested that genome sequencing alone cannot give sufficient information to explain or predict complex phenotypes , as it does not consider the additional factors that affect protein expression such as epigenetics (Borrell and Gagneux 2011; Jelier et al. 2011; Beltrao et al. 2012; Bierne et al. 2012). However, here we have shown that using robust statistical techniques on large collections of sequenced isolates alongside machine learning approaches can yield desired results. "
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    ABSTRACT: Microbial virulence is a complex and often multifactorial phenotype, intricately linked to a pathogen's evolutionary trajectory. Toxicity, the ability to destroy host cell membranes, and adhesion, the ability to adhere to human tissues, are the major virulence factors of many bacterial pathogens, including Staphylococcus aureus. Here, we assayed the toxicity and adhesiveness of 90 MRSA (methicillin resistant S. aureus) isolates and found that while there was remarkably little variation in adhesion, toxicity varied by over an order of magnitude between isolates, suggesting different evolutionary selection pressures acting on these two traits. We performed a genome-wide association study (GWAS) and identified a large number of loci, as well as a putative network of epistatically interacting loci, that significantly associated with toxicity. Despite this apparent complexity in toxicity regulation, a predictive model based on a set of significant single nucleotide polymorphisms (SNPs) and insertion and deletions events (indels) showed a high degree of accuracy in predicting an isolate's toxicity solely from the genetic signature at these sites. Our results thus highlight the potential of using sequence data to determine clinically relevant parameters and have further implications for understanding the microbial virulence of this opportunistic pathogen.
    Genome Research 04/2014; 24(5). DOI:10.1101/gr.165415.113 · 14.63 Impact Factor
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