ABSTRACT
Early life adversity plays a critical role in the emergence of borderline personality disorder (BPD) and this could occur through epigenetic programming. In this perspective, we aimed to determine whether childhood maltreatment could durably modify epigenetic processes by the means of a whole-genome methylation scan of BPD subjects. Using the Illumina Infinium® HumanMethylation450 BeadChip, global methylation status of DNA extracted from peripheral blood leucocytes was correlated to the severity of childhood maltreatment in 96 BPD subjects suffering from a high level of child adversity and 93 subjects suffering from major depressive disorder (MDD) and reporting a low rate of child maltreatment. Several CpGs within or near the following genes (IL17RA, miR124-3, KCNQ2, EFNB1, OCA2, MFAP2, RPH3AL, WDR60, CST9L, EP400, A2ML1, NT5DC2, FAM163A and SPSB2) were found to be differently methylated, either in BPD compared with MDD or in relation to the severity of childhood maltreatment. A highly relevant biological result was observed for cg04927004 close to miR124-3 that was significantly associated with BPD and severity of childhood maltreatment. miR124-3 codes for a microRNA (miRNA) targeting several genes previously found to be associated with BPD such as NR3C1. Our results highlight the potentially important role played by miRNAs in the etiology of neuropsychiatric disorders such as BPD and the usefulness of using methylome-wide association studies to uncover such candidate genes. Moreover, they offer new understanding of the impact of maltreatments on biological processes leading to diseases and may ultimately result in the identification of relevant biomarkers.
Subject(s)
Borderline Personality Disorder/genetics , Child Abuse/psychology , DNA Methylation , Adult , Child , Depressive Disorder, Major/genetics , Female , Genetic Markers/genetics , Genome-Wide Association Study , Humans , Male , Psychiatric Status Rating ScalesABSTRACT
In Staphylococcus aureus, the role of the GGDEF domain-containing protein GdpS remains poorly understood. Previous studies reported that gdpS mutant strains had decreased biofilm formation due to changes in icaADBC expression that were independent of cyclic-di-GMP levels. We deleted gdpS in three unrelated S. aureus isolates, and analyzed the resultant mutants for alterations in biofilm formation, metabolism and transcription. Dynamic imaging during biofilm development showed that GdpS inhibited early biofilm formation in only two out of the three strains examined, without affecting bacterial survival. However, quantification of biofilm formation using crystal violet staining revealed that inactivation of gdpS affected biofilm formation in all three studied strains. Extraction of metabolites from S. aureus cells confirmed the absence of cyclic-di-GMP, suggesting that biofilm formation in this species differs from that in other Gram-positive organisms. In addition, targeted mutagenesis demonstrated that the GGDEF domain was not required for GdpS activity. Transcriptomic analysis revealed that the vast majority of GGDEF-regulated genes were involved in virulence, metabolism, cell wall biogenesis and eDNA release. Finally, expression of lrgAB or deletion of cidABC in a strain lacking gdpS confirmed the role of GdpS on regulation of eDNA production that occurred without an increase in cell autolysis, but with a late increase in holin-mediated autolysis, in the presence of high oxacillin concentrations. In summary, S. aureus GdpS contributes to cell-to-cell interactions during early biofilm formation by influencing expression of lrgAB and cidABC mediated eDNA release. We conclude that GdpS acts as a negative regulator of eDNA release.
Subject(s)
Bacterial Proteins/metabolism , Biofilms/growth & development , DNA, Bacterial/metabolism , Gene Expression Regulation, Bacterial , Staphylococcus aureus/physiology , Transcription Factors/metabolism , Bacterial Proteins/genetics , Gene Deletion , Gene Expression Profiling , Humans , Optical Imaging , Staphylococcus aureus/genetics , Transcription Factors/genetics , Transcription, GeneticABSTRACT
CASE PRESENTATION: A 46-year-old man suffering from progressive deafness since childhood received a Clarion 90 K cochlear implant with the HiRes preformed electrode in his left ear in October 2006. A persistent Staphylococcus aureus infection failed to be treated with corticoids, amoxicillin/ clavulanate, ciprofloxaxin, and rifampin. The processor was removed on July 2007. INTERVENTIONS: The removed cochlear implant processor was treated with different reagents, with the aim of detecting a S. aureus and S. aureus biofilm: (1) fluorescein-coupled Fc of anti-human serum, (2) polyclonal anti-polysaccharide intercellular adhesion antibodies coupled to Alexa Fluor 568 goat anti-rabbit immunoglobulin (Ig)G, (3) crystal violet, (4) methylene blue, (5) acridine orange, (6) Gram stain, and (7) live/dead fluorescent stain. RESULTS: S. aureus and the major constituent of the S. aureus biofilm, the polysaccharide intercellular adhesion, were detected on the surface of the implant. S. aureus was isolated after a simple contact between the implant and a solid growth medium. The ability of the isolated S. aureus strain to produce biofilm in vitro was confirmed. INTERPRETATION: S. aureus biofilm was documented on the implant. Initial bacterial colonization could be related to the pocket of the removable magnet. Colonies of S. aureus without biofilm were found attached to the electrode wire. CONCLUSION: We report one case of a S. aureus biofilm infection documented on a cochlear implant, as assessed by immuno-microscopy. The biofilm was likely responsible for the persistent infection which manifested for many months after the implant surgery and could explain the unusual bacterial phenotypic resistance against administered antimicrobial agents.
