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Borrelia burgdorferi infection induces long-term memory-like responses in macrophages with tissue-wide consequences in the heart

ABSTRACT: Lyme carditis is an extracutaneous manifestation of Lyme disease characterized by episodes of atrioventricular block of varying degrees and other less reported cardiomyopathies. The molecular changes associated with the response to Borrelia burgdorferi over the course of infection are poorly understood. Here, we identify broad transcriptomic and proteomic changes in the heart during infection that reveal a profound downregulation of mitochondrial components. We also characterize the long-term functional modulation of macrophages exposed to live bacteria, characterized by an augmented glycolytic output, increased spirochetal binding and internalization, and reduced IRF-4-dependent inflammatory responses. In vitro, glycolysis inhibition reduces the production of TNF by memory macrophages whereas in vivo, it produces the reversion of the Irf4-induced memory phenotype, the recovery of tissue mitochondrial components, and decreased inflammation and spirochetal burdens. These results show that B. burgdorferi induces long-term, memory-like responses in macrophages with tissue-wide consequences that are amenable to be manipulated in vivo.

ORGANISM(S): Mus musculus

PROVIDER: GSE152168 | GEO | 2020/12/22

REPOSITORIES: GEO

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Macrophage responses to persistent Borrelia burgdorferi stimulation modulates host inflammation and results in tissue-wide transcriptional and proteomic changes during Lyme carditis

Project description:Lyme carditis is an extracutaneous manifestation of Lyme disease characterized by episodes of atrioventricular block of varying degrees and other less reported cardiomyopathies. The molecular changes associated with the response to Borrelia burgdorferi over the course of infection are poorly understood. Here, we identify broad transcriptomic and proteomic changes in the heart during infection that reveal a profound downregulation of mitochondrial components. We also characterize the long-term functional modulation of macrophages exposed to live bacteria, characterized by an augmented glycolytic output, increased spirochetal binding and internalization, and reduced IRF-4-dependent inflammatory responses. In vitro, glycolysis inhibition reduces the production of TNF by memory macrophages whereas in vivo, it produces the reversion of the Irf4-induced memory phenotype, the recovery of tissue mitochondrial components, and decreased inflammation and spirochetal burdens. These results show that B. burgdorferi induces long-term, memory-like responses in macrophages with tissue-wide consequences that are amenable to be manipulated in vivo.

2021-09-09 | PXD019605 | Pride

RNAseqcharacterization ofB. burgdorferi-inducedinnate immune memoryandregulation ofLyme carditis through Acod1

Project description:Borrelia burgdorferi (Bb), which causes Lyme disease, establishes long term infection and leads to disease manifestations that are mostly a result of host immune responses to the pathogen. Disease symptoms often resolve without treatment, suggesting innate immune memory may play a role in dampening inflammation over time. We used an in vitro model of repeated stimulations in macrophage and performed RNA sequencing on acute and memory states. We categorized differentially expressed genes based on their response to acute infection as well as their memory response compared to acute. We discuss four expression subsets representing important cellular changes to repeated stimulation and focus on genes that are negative regulators of inflammation induced during the acute phase and mediate long-term immunosuppression. We identified Aconitate decarboxylase 1 (Acod1), a negative regulator of inflammatory responses, and confirmed its role during in vivo long-term infection with Bb, with a specific role in Lyme carditis.

2023-11-01 | GSE236149 | GEO

Macrophage training to Borrelia burgdorferi governs cardiac inflammation in the mammalian host [RNA-seq]

Project description:Macrophage exposure to vaccine or vaccine-like formulations results in disparate secondary responses. We have identified the transcriptomic and metabolic changes associated with the memory response of macrophages to Borrelia burgdorferi, an extracellular pathogen able to establish long-term infections in mammals. Memory macrophages show an enhanced ability to bind and internalize the spirochete with decreased inflammatory responses, in part regulated by Irf4. Experienced macrophages also show an augmented glycolytic output. In vivo, glycolysis inhibition results in decreased cardiac inflammation and reduced expression of Irf4. Our data show that B. burgdorferi induces long-term, memory-like responses that are amenable to be manipulated in vivo.

2021-01-21 | GSE125503 | GEO

Regulation of Borrelia burgdorferi-induced macrophage activity by spirochetal-regulated surface receptors

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2019-12-06 | PXD012854 | Pride

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

Epigenomic landscape of Lyme disease spirochetes reveals novel motifs

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2021-03-24 | GSE169460 | 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

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

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

Project description: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.

2018-02-13 | GSE102748 | GEO

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

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