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Borrelia burgdorferi, the Lyme disease spirochete, possesses genetically-encoded responses to doxycycline, but not to amoxicillin.

ABSTRACT: Purpose: To determine whether Borrelia burgdorferi, the spirochetal agent of Lyme disease, responds to sub-lethal doses of antibiotics. Methods: mRNA profiles of Borrelia burgdorferi were compared after subculturing in 0.2μg/mL amoxicillin, 0.2μg/mL doxycycline, or media control for 3h or 24h (n=3 per group) by paired-end sequencing using the Illumina NextSeq 500. The sequence reads were aligned using Salmon aligner followed by DESeq2 for differential expression analysis. Results: After culturing for 24 h in a sub-lethal concentration of doxycycline, there were significant increases in a substantial number of transcripts for proteins that are involved with translation. Bacteria continued to elongate, but appeared to be defective in septation and formed filaments. In contrast, incubation with sublethal concentration of amoxicillin led to membrane blebbing and swelling, indicative of cell wall disruption, but no significant changes in levels of any bacterial transcript. Conclusion: We conclude that B. burgdorferi has a mechanism(s) that detects translational inhibition by doxycycline, and increases production of translational machinery in compensation. In contrast, The absence of response to the inhibition of cell wall synthesis by amoxicillin implies that B. burgdorferi lacks a mechanism to assess cell wall integrity.

ORGANISM(S): Borreliella burgdorferi

PROVIDER: GSE197338 | GEO | 2022/03/08

REPOSITORIES: GEO

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Borrelia burgdorferi, the Lyme disease spirochete, possesses genetically-encoded responses to doxycycline, but not to amoxicillin.

Project description:Borrelia burgdorferi, the Lyme disease spirochete, possesses genetically-encoded responses to doxycycline, but not to amoxicillin.

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Project description:Comparison of the whole genome gene expression level of an amoxicillin resistant E. coli strain with the wildtype it was derived from. The process of amoxicillin adaptation of E. coli MG1655 wildtype cells is further descibed in van der Horst, M, J.M. Schuurmans, M. C. Smid, B. B. Koenders, and B. H. ter Kuile (2011) in Microb. Drug Resist. 17:141-147. Resistance to amoxicillin was induced in E. coli by growth in the presence of stepwise increasing antibiotic concentrations. To investigate consequences of the aquisition of amoxicillin resistance the transcriptomic profile of sensitive and resistant cells was compared in the absence and presence of sub-inhibitory (0.25xMIC) amoxicillin concentrations was compared. Total RNA of 3 biological replicates of E. coli MG1655 wildtype cells and amoxicillin resistant cells cultured with (0.25xMIC) or without amoxicillin was hybridized on a 12x135k custom designed microarraychip against one common reference.

2013-05-27 | E-GEOD-47221 | biostudies-arrayexpress

Expression analysis of an amoxicillin resistant Escherichia coli strain

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Transcription profiling of human umbilical vein endothelial cells treated with Interferon-gamma (IFN-g), Borrelia burgdorferi or both IFN-g and Borrelia or untreated to investigate immune responses to Lyme disease

Project description:Borrelia burgdorferi, the agent of Lyme disease, promotes pro-inflammatory changes in endothelium that lead to the recruitment of leukocytes. The host immune response to infection results in increased levels of IFN-gamma in the serum and lesions of Lyme disease patients that correlate with greater severity of disease. Therefore, the effect of IFN-gamma on the gene expression profile of primary human endothelial cells exposed to B. burgdorferi was determined. B. burgdorferi and IFN-gamma synergistically augmented the expression of 34 genes, seven of which encode chemokines. Six of these (CCL7, CCL8, CX3CL1, CXCL9, CXCL10, and CXCL11) attract T lymphocytes, and one (CXCL2) is specific for neutrophils. Synergistic production of the attractants for T cells was confirmed at the protein level. IL-1beta, TNF-alpha, and LPS also cooperated with IFN-gamma to induce synergistic production of CXCL10 by endothelium, indicating that IFN-gamma potentiates inflammation in concert with a variety of mediators. An in vitro model of the blood vessel wall revealed that an increased number of human T lymphocytes traversed endothelium exposed to B. burgdorferi and IFN-gamma, as compared to unstimulated endothelial monolayers. In contrast, addition of IFN-gamma diminished the migration of neutrophils across B. burgdorferi-activated endothelium. IFN-gamma thus alters gene expression by endothelium exposed to B. burgdorferi in a manner that promotes recruitment of T cells and suppresses that of neutrophils. This modulation may facilitate the development of chronic inflammatory lesions in Lyme disease. Experiment Overall Design: Human umbilical vein endothelial cells (HUVEC) were stimulated with Interferon-gamma (IFN-g), Borrelia burgdorferi or both IFN-g and Borrelia or were left unstimulated. Affymetrix HGU133 plus 2.0 slides were used in duplicate for each condition.

2008-06-14 | E-GEOD-6092 | biostudies-arrayexpress

Identification of the differences between gene expression in normal human dermal fibroblasts (NHDF cell line) infected with Borrelia burgdorferi sensu lato spirochetes

Project description:The similarity of Lyme borreliosis to other diseases and the complex pathogenesis cause diagnostic and therapeutic difficulties. Changes at the cellular and molecular level after Borrelia sp. infection remain still poorly understood. Therefore, the present study focused on the gene expression in human dermal fibroblasts in differentiation of infection with Borrelia garinii, Borrelia afzelii and Borrelia burgdorferi sensu stricto spirochetes. For microarray analysis 10 samples were used: 3 control samples - K, 2 samples of NHDF cells infected with Borrelia garinii - G, 2 samples of NHDF cells infected with Borrelia afzelii - A and 3 samples of NHDF cells infected with Borrelia burgdorferi sensu stricto - SS.

2015-05-12 | E-GEOD-68741 | biostudies-arrayexpress

Epigenomic landscape of Lyme disease spirochetes reveals novel motifs

Project description:Borrelia burgdorferi, the etiological agent of Lyme disease, persists in nature through an enzootic cycle consisting of a vertebrate host and an Ixodes tick vector. The sequence motifs modified by two well-characterized restriction/modification loci of B. burgdorferi type strain B31 were recently described, but the methylation profiles of other Lyme disease Borrelia have not been characterized. Herein, the methylomes of B. burgdorferi type strain B31 and 7 clonal derivatives, along with B. burgdorferi N40, B. burgdorferi 297, B. burgdorferi CA-11, B. afzelii PKo, B. afzelii BO23, and B. garinii PBr, were defined through PacBio SMRT sequencing. This analysis revealed 9 novel sequence motifs methylated by the plasmid-encoded restriction/modification enzymes of these Borrelia strains. Furthermore, while a previous analysis of B. burgdorferi B31 revealed an epigenetic impact of methylation on the global transcriptome, the current data contradict those findings; our analyses of wild-type B. burgdorferi B31 revealed no consistent differences in gene expression among isogenic derivatives lacking one or more restriction/modification enzyme(s).

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AMOXICILLIN HAPTENATION OF α-ENOLASE

Project description:Allergic reactions to antibiotics are a major concern in the clinic, with almost 15% of the patients presenting with adverse reactions against β-lactam antibiotics. One of the mechanisms involved in this outcome is the modification of proteins by covalent binding of the drug (haptenation). Hence, the interest in identifying the corresponding serum and cellular protein targets. Importantly, haptenation susceptibility and extent can be modulated by the context, including factors affecting protein conformation or the occurrence of other posttranslational modifications. We previously identified the glycolytic enzyme α-enolase as a target for haptenation by amoxicillin, both in cells and in the extracellular milieu. Here, we performed an in vitro study to analyze amoxicillin haptenation of α-enolase using gel-based and activity assays. Moreover, the possible interplay or interference of amoxicillin haptenation with acetylation was also studied in 1D- and 2D-gels that showed decreased haptenation and displacement of the haptenation signal to lower pI spots upon chemical acetylation, respectively. Mass spectrometry identified lysine 239 as the amoxicillin target residue on α enolase, thus suggesting a selective haptenation under our conditions. The amoxicillin binding site and the surrounding interactions were investigated using the α-enolase crystal structure and molecular docking. Altogether, the results obtained provide the basis for the design of novel diagnostic tools or approaches in the study of amoxicillin-induced allergic reactions.

2022-02-17 | PXD029712 | Pride

Borrelia burgdorferi induces a type I interferon response during early stages of disseminated infection in mice

Project description:Background: Lyme borrelia genotypes differ in their capacity to cause disseminated disease. Gene array analysis was employed to profile the host transcriptome induced by Borrelia burgdorferi strains with different capacities for causing disseminated disease in the blood of C3H/HeJ mice during early infection. Results: Borrelia burgdorferi B515, a clinical isolate that causes disseminated infection in mice, differentially regulated 236 transcripts (P<0.05 by ANOVA, with fold change of at least 2). The 216 significantly induced transcripts included IFN-responsive genes and genes involved in immunity and inflammation. In contrast, B. burgdorferi B331, a clinical isolate that causes transient skin infection but does not disseminate in C3H/HeJ mice, stimulated changes in only a few genes (1 induced, 4 repressed). Transcriptional regulation of type I IFN and IFN-related genes was measured by quantitative RT-PCR in mouse skin biopsies collected from the site of infection 24 hours after inoculation with B. burgdorferi. The mean values for transcript of Ifnb, Cxcl10, Gbp1, Ifit1, Ifit3, Irf7, Mx1, and Stat2, were found to be significantly increased in B. burgdorferi strain B515-infected mice relative to the control group. In contrast, transcription of these genes was not significantly changed in response to B. burgdorferi strain B331 or B31-4, a mutant that is unable to disseminate. Conclusions: These results establish a positive association between the disseminating capacity of B. burgdorferi and early type I IFN induction in a murine model of Lyme disease.

2016-03-25 | E-MTAB-3325 | biostudies-arrayexpress

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