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Gene expression profiling during active Lyme arthritis development (22 days post infection with B. burgdorferi) in CD45 negative cells isolated from joint tissue of highly genetically similar mouse strains: B6, ISRCL4, and ISRCL3

ABSTRACT: Previously, using a forward genetic approach we identified B. burgdorferi arthritis-associated locus 1 (Bbaa1), a quantitative trait locus on Chr4, which physically encompasses the type I IFN gene cluster and regulates Lyme arthritis through heightened type I IFN production. Reciprocal radiation chimeras between B6.C3-Bbaa1 and B6 mice revealed that arthritis is initiated by radiation-sensitive cells, but orchestrated by radiation-resistant components of joint tissue. Advanced congenic lines were developed to reduce the physical size of the Bbaa1 interval, and RNA-seq of resident CD45- joint cells from advanced interval specific recombinant congenic lines (ISRCL4 and ISRCL3) identified myostatin as uniquely upregulated in association with Bbaa1 arthritis development. Our manuscript further demonstrates that myostatin expression is linked to IFN-β production, and in vivo inhibition of myostatin suppresses Lyme arthritis in the reduced interval Bbaa1 congenic mice, formally implicating myostatin as a novel downstream mediator of joint-specific inflammatory response to B. burgdorferi.

ORGANISM(S): Mus musculus

PROVIDER: GSE102748 | GEO | 2018/02/13

REPOSITORIES: GEO

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The Cdkn2a gene product ARF is a critical regulator of IFNb mediated Lyme arthritis

Project description:Lyme disease is caused by infection with Borrelia burgdorferi, with a spectrum of clinical disorders. Murine studies with B6 and C3H mice have demonstrated that genetic differences in the host response play an essential role in regulating the severity of Lyme arthritis. C3H mice generate a robust induction of type I IFN response in joint tissue at one week of infection which leads to severe Lyme arthritis at 4 weeks post-infection, while B6 mice develop mild disease without a type I IFN profile. We used a forward genetic approach and identified B. burgdorferi arthritis- associated locus 1 (Bbaa1) on Chr4, which includes type I IFN cluster. B6.C3-Bbaa1 congenic mice display more severe Lyme arthritis than B6 mice. The blocking of type I IFN receptor and the IFNb subtype in Bbaa1 mice suppressed arthritis back to B6 level, so we concluded the Bbaa1 locus intrinsically controls IFNb production, and the differential expression of IFNb controls the severity of Lyme arthritis. However, the IFNb genes of C3H and B6 mice are identical, prompting focus on other genetic factors within the Bbaa1 locus as regulators of IFNb. Reciprocal radiation chimeras between B6.C3-Bbaa1 and B6 mice revealed myeloid cells in the joint tissue as IFNb initiators. Advanced congenic lines were generated to reduce the genetic contribution from C3H Bbaa1 region. RNA-seq of bone marrow-derived macrophages (BMDMs) from B6 and advanced interval specific recombinant congenic lines, ISRCL3 and ISRCL4, revealed novel candidates that may regulate Ifnb. In this study, we identify the Cdkn2a gene encoded ARF as a critical regulator of IFNb mediated Lyme arthritis, and investigate mechanistic interactions that modulate IFNb expression in Lyme arthritis development.

2022-02-17 | GSE181071 | GEO

Expression profiling of joint tissue from C3H and interval specific congenic mouse lines post- B. burgdorferi infection

Project description:Gene expression profile of joint tissue from C3H and interval specific congenic mouse lines (ISCL) following infection with Borrelia burgdorferi Congenic lines of mice generated between C3H and C57BL/6 with penetrant arthritis severity phenotype were infected with B. burgdorferi Joint tissue was collected from uninfected control mice and from mice infected for 1 week, RNA was prepared and gene expressed analyzed by Affymetrix microarray.

2009-06-22 | GSE16195 | GEO

Transcription profiling of mouse joint tissue from C3H and interval specific congenic mouse lines post- B. burgdorferi infection

Project description:Gene expression profile of joint tissue from C3H and interval specific congenic mouse lines (ISCL) following infection with Borrelia burgdorferi; Congenic lines of mice generated between C3H and C57BL/6 with penetrant arthritis severity phenotype were infected with B. burgdorferi; Joint tissue was collected from uninfected control mice and from mice infected for 1 week, RNA was prepared and gene expressed analyzed by Affymetrix microarray. Experiment Overall Design: Each sample was comprised of pooled RNA from at least 5 female mice of each genotype.

2009-07-01 | E-GEOD-16195 | biostudies-arrayexpress

Transcription profiling of mouse model of Lyme disease

Project description:The murine model of Lyme disease provides a unique opportunity to study the localized host response to similar stimulus, B. burgdorferi, in the joints of mice destined to develop severe arthritis (C3H) or mild disease (C57BL/6). Pathways associated with the response to infection and the development of Lyme arthritis were identified by global gene expression patterns using oligonucleotide microarrays. A robust induction of IFN responsive genes was observed in severely arthritic C3H mice at one week of infection, which was absent from mildly arthritic C57BL/6 mice. In contrast, infected C57BL/6 mice displayed a novel expression profile characterized by genes involved in epidermal differentiation and wound repair, which were decreased in the joints of C3H mice. These expression patterns were associated with disease state rather than inherent differences between C3H and C57BL/6 mice, as C57BL/6-IL10-/- mice infected with B. burgdorferi develop more severe arthritis that C57BL/6 mice and displayed an early gene expression profile similar to C3H mice. Gene expression profiles at two and four weeks post infection revealed a common response of all strains that was likely to be important for the host defense to B. burgdorferi and mediated by NF-kB-dependent signaling. The gene expression profiles identified in this study add to the current understanding of the host response to B. burgdorferi and identify two novel pathways that may be involved in regulating the severity of Lyme arthritis. Experiment Overall Design: Expression profiling of ankle tissues of C3H, C57BL/6, and C57BL/6-IL10-/- mice infected with B. burgdorfer (0, 1, 2, and 4 weeks post-infection)

2008-06-14 | E-GEOD-6055 | biostudies-arrayexpress

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

Gene Expression Profiling Reveals Unique Pathways Associated with Differential Severity of Lyme Arthritis

2006-12-14 | GSE6055 | GEO

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

IFN-gamma alters the response of Borrelia burgdorferi-activated endothelium to favor chronic inflammation

2007-01-05 | GSE6092 | GEO

RNA sequencing of a C57BL/6J-DBA/2J (B6.D2) congenic mouse and C57BL/6J (B6) wild-type littermates reveals cis and trans differences in gene expression

Project description:We previously utilized interval-specific congenic lines derived from C57BL/6J (B6) and DBA/2J (D2) alleles to fine map a quantitative trait locus (QTL) influencing methamphetamine (MA)- induced locomotor activity. We identified a 0.23 MB critical interval on chromosome 11 containing only two protein coding genes, Rufy1 and Hnrnph1. Notably, Rufy1 contains three missense SNPs and Hnrnph1 contains 1 SNP near the 5’ UTR. In an effort to identify the molecular mechanisms that bridge genetic variation with behavior, we conducted transcriptome analysis via mRNA sequencing (RNA-seq) in a B6.D2 congenic line (chr.11: 50-60 Mb) that captures the QTL. There was an overrepresentation of cis-regulated, differentially expressed genes within the congenic interval (4 out of 92 differentially expressed genes; FDR < 0.05) and widespread genomic regulation on all autosomes.

2015-12-11 | GSE66366 | GEO

Increased physical activity accompanies carbohydrate preference in a B6.CAST-17 sub-congenic mouse strain

Project description:A C57BL6/J (B6) x CAST/Ei (CAST) strain intercross was used to identify the first mammalian QTL for macronutrient-specific intake (carbohydrate and fat) and for total energy intake. A region on proximal Chromosome 17 revealed two significant QTL that co-localized for increased macronutrient intake-carbohydrate (Mnic1) and total kilocalorie intake (Kcal2), adjusted for body weight. An interval-specific congenic strain, B6.CAST-17, was then developed which verified the QTL. A new sub-congenic strain was developed which retained the linked traits. Important new findings emerged shows that this congenic interval confers an activity phenotype, i.e., mice carrying the differential segment have 20% higher spontaneous physical activity levels compared with the host B6 strain. We hypothesize that this Chromosome 17 QTL is either encoded by a single gene locus that determines both food intake and physical activity, or by two or more genes, each determining a sub-phenotype of energy balance. Microarray analysis of skeletal muscle and hypothalamus in congenic and wild type B6 mice was carried out to identify potential candidate genes for the activity and food intake behavior. Keywords: macronutrient-specific intake, sub-congenic strain

2009-02-12 | GSE10517 | GEO

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