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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

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

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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

Changes in gene expression of human monocyte derived dendritic cells exposed to live Borrelia burdgorferi or LTA

Project description:Dendritic cells bridge the innate and adaptive immune response by serving as sensors of infection and as the primary antigen presenting cells responsible for the initiation of the T cell response against invading pathogens. Initial interactions between B. burgdorferi, the causative agent of Human Lyme disease, and dendritic cells remain largely unexplored. To address this, we cultured monocyte-derived dendritic cells (moDCs) with and without the Toll-Like Receptor 2 agonist LTA or live B. burgdorferi and examined changes in gene expression using RNAseq. We observed that B. burgdorferi exposed moDCs display a distinct and novel gene expression signature that differs from that induced by the Toll-Like Receptor 2 reference agonist. Collectively these studies indicate that the interaction of live B. burgdorferi with mo-DCs promotes a unique mature DC phenotype that likely impacts the nature of the adaptive T cell response generated in human Lyme disease.

2023-06-02 | GSE211551 | GEO

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