Abstract
Anaplasma phagocytophilum, an obligate intracellular prokaryote, infects neutrophils, and alters cardinal functions via reprogrammed transcription. Large contiguous regions of neutrophil chromosomes are differentially expressed during infection. Secreted A. phagocytophilum effector AnkA transits into the neutrophil or granulocyte nucleus to complex with DNA in heterochromatin across all chromosomes. AnkA binds to gene promoters to dampen cis-transcription and also has features of matrix attachment region (MAR)-binding proteins that regulate three-dimensional chromatin architecture and coordinate transcriptional programs encoded in topologically-associated chromatin domains. We hypothesize that identification of additional AnkA binding sites will better delineate how A. phagocytophilum infection results in reprogramming of the neutrophil genome. Using AnkA-binding ChIP-seq, we showed that AnkA binds broadly throughout all chromosomes in a reproducible pattern, especially at: (i) intergenic regions predicted to be MARs; (ii) within predicted lamina-associated domains; and (iii) at promoters ≤ 3000 bp upstream of transcriptional start sites. These findings provide genome-wide support for AnkA as a regulator of cis-gene transcription. Moreover, the dominant mark of AnkA in distal intergenic regions known to be AT-enriched, coupled with frequent enrichment in the nuclear lamina, provides strong support for its role as a MAR-binding protein and genome “re-organizer.” AnkA must be considered a prime candidate to promote neutrophil reprogramming and subsequent functional changes that belie improved microbial fitness and pathogenicity.
Highlights
Intracellular bacteria, such as Anaplasma phagocytophilum, evolved mechanisms for survival within, subversion of host functions, or symbiotic relationships with their eukaryotic hosts
We previously showed that A. phagocytophilum infection leads to altered chromatin structure at the promoters of many host defense genes driven by AnkA binding (Garcia-Garcia et al, 2009a,b)
We showed that transfection of AnkA alone, a type IV system secretion substrate, mimics many transcriptional changes observed with infection, including those associated with direct binding to host DNA in many genomic regions (Garcia-Garcia et al, 2009b)
Summary
Intracellular bacteria, such as Anaplasma phagocytophilum, evolved mechanisms for survival within, subversion of host functions, or symbiotic relationships with their eukaryotic hosts. While tick-transmitted A. phagocytophilum infection results in clinical disease manifestations in some animals and humans, referred to as granulocytic anaplasmosis, its mere occupancy in the most abundant host defense cell, the neutrophil, is an intriguing evolutionary adaptation, owing to its role in innate immunity where it recognizes and kill microbes (Scapini and Cassatella, 2014). Major alterations induced by A. phagocytophilum infection of human neutrophils impact antimicrobial responses such as respiratory burst, phagocytosis, margination, and emigration across the endothelium, delayed apoptosis and increased production of proinflammatory cytokines, chemokines, and proteases (Carlyon et al, 2002; Carlyon and Fikrig, 2003, 2006; Choi et al, 2005; Dumler et al, 2005; Garyu et al, 2005). Infection is strongly associated with increased transcription from a number of cytokine and chemokine genes, including IL1A and CXCL8 (IL-8), that contribute to recruitment of new neutrophil hosts, and to inflammatory tissue injury and disease (Klein et al, 2000; Akkoyunlu et al, 2001; Scorpio et al, 2004)
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