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

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE125503 | GEO | 2021/01/21

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.

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

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A multi-omic analysis reveals a regulatory role of CD180 during the response of macrophages to Borrelia burgdorferi [RNA-Seq]

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

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

| PRJNA638542 | ENA

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DksA controls the response of the Lyme disease spirochete Borrelia burgdorferi to starvation

Project description:The pathogenic spirochete Borrelia burgdorferi senses and responds to diverse environmental challenges, including changes in nutrient availability, throughout its natural infectious cycle in Ixodes spp. ticks and mammalian hosts. This study examined the role of the putative DnaK suppressor protein (DksA) in the transcriptional response of B. burgdorferi to starvation. Wild-type and dksA-deficient B. burgdorferi strains were subjected to starvation by shifting mid-logarithmic cultures grown in BSK-II medium to serum-free RPMI medium for six hours under microaerobic conditions (5% CO2, 3% O2). Microarray analyses of wild-type B. burgdorferi revealed that genes encoding flagellar components, ribosomal proteins, and DNA replication machinery were downregulated in response to starvation. DksA mediated transcriptomic responses to starvation in B. burgdorferi as the dksA-deficient B. burgdorferi strain differentially expressed only 47 genes in response to starvation compared to the 500 genes differentially expressed by wild-type strains. Consistent with a role for DksA in the starvation response of B. burgdorferi, fewer CFUs were observed for dksA-deficient spirochetes after prolonged starvation in RPMI medium compared to wild-type B. burgdorferi. Transcriptomic analyses revealed a partial overlap between the DksA regulon and the regulon of the guanosine tetraphosphate and guanosine pentaphosphate [(p)ppGpp] synthase RelBbu, while the DksA regulon also included many plasmid-borne genes. Corresponding to a DksA-(p)ppGpp regulatory relationship, (p)ppGpp levels were constitutively elevated in the dksA-deficient strain compared to the wild-type strain. Together, these data indicate that DksA directs the stringent response with a regulatory interplay with (p)ppGpp that is fundamental to B. burgdorferi responses to the environment.

2018-12-18 | GSE119023 | GEO

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