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.
Highlights
In order to infect mammalian hosts, bacterial pathogens evolved an array of mechanisms that serve to create an environment conducive for survival, replication, and spread
While many bacterial species survive in an extracellular environment, intracellular pathogens must be capable of both entering their host cells undetected and altering the cellular milieu in order to replicate
Inhibition of histone deacetylase-1 (HDAC1), but not HDAC2 expression by siRNA or pharmacologic inhibition of HDAC activity impairs A. phagocytophilum propagation, whereas overexpression leads to increased intracellular propagation (Garcia-Garcia et al, 2009a). We modeled this process by using the wild type CYBB promoter, to which ankyrin A (AnkA) binds, and mutated forms unable to bind AnkA in order to demonstrate that AnkA binding leads to HDAC1 recruitment and silencing of expression at CYBB (Garcia-Garcia et al, 2009b)
Summary
In order to infect mammalian hosts, bacterial pathogens evolved an array of mechanisms that serve to create an environment conducive for survival, replication, and spread. While many bacterial species survive in an extracellular environment, intracellular pathogens must be capable of both entering their host cells undetected and altering the cellular milieu in order to replicate. 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). Histone acetylation, which imparts a negative charge, is predominantly associated with an open configuration where promoters are accessed by RNA polymerases. Histone methylation or phosphorylation which impart a positive charge, cause DNA to more tightly associate with histone proteins, reducing promoter accessibility to transcription activating machinery. It is no surprise that bacterial-derived proteins have evolved to interfere with host gene expression that improves bacterial fitness
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