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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
Project description:Macrophage training to Borrelia burgdorferi governs cardiac inflammation in the mammalian host
| PRJNA516655 | ENA
Project description:Macrophage training to Borrelia burgdorferi governs cardiac inflammation in the mammalian host [RNA-seq]
| PRJNA516652 | ENA
Project description:Summary Borrelia burgdorferi (Bb), the Lyme disease spirochaete, encodes a potential ferric uptake regulator (Fur) homologue, BosR (BB0647). Thus far, a role for BosR in Bb metabolism, gene regulation or pathogenesis has not been determined, largely due to the heretofore inability to inactivate bosR in low-passage, infectious Bb isolates. Herein, we report the generation of the first bosR-deficient mutant in a virulent strain of Bb. Whereas the bosR mutant persisted normally in ticks, the mutant was unable to infect mice, indicating that BosR is essential for Bb infection of a mammalian host. Moreover, transcriptional profiling of the bosR mutant showed that a number of genes were either positively or negatively influenced by BosR deficiency, suggesting that BosR may function both as a global repressor and activator in Bb. Strikingly, our study showed that BosR controls the expression of two major virulence-associated Bb lipoproteins, OspC and DbpA, likely via an influence on the alternative sigma factor, RpoS. This study thus not only has elucidated another key virulence gene of Bb, but also provides new insights into a previously unknown layer of gene regulation governing RpoS in Bb.
| S-EPMC2831293 | biostudies-literature
Project description:Borrelia burgdorferi encodes a functional homolog of canonical Lon protease termed Lon-2. To date, the contribution of Lon-2 to B. burgdorferi fitness and infection remains unexplored. Herein, we showed that expression of lon-2 was highly induced during animal infection, suggesting that Lon-2 is important for B. burgdorferi infection. We further generated a lon-2 deletion mutant. Compared with that of wild-type (WT) strain, the infectivity of the mutant was severely attenuated in a murine infection model. Although no growth defect was observed for the mutant in normal BSK-II medium, resistance of the lon-2 mutant to osmotic stress was markedly reduced. In addition, when exposed to tert-Butyl hydroperoxide, survival of the lon-2 mutant was impaired. In addition, we found that the protein levels of RpoS and RpoS-dependent OspC were decreased in the mutant. All these phenotypes were restored to WT or near-WT levels when lon-2 mutation was complemented in cis. Taken together, these results demonstrate that Lon-2 is critical for B. burgdorferi to establish infection and to cope with environmental stresses. This study provides a foundation for further uncovering the direct link between the dual roles of Lon-2 in protein quality control and bacterial pathogenesis.
| S-EPMC8363874 | biostudies-literature
Project description:Borrelia burgdorferi, the agent of Lyme disease, has cholesterol and cholesterol-glycolipids that are essential for bacterial fitness, are antigenic, and could be important in mediating interactions with cells of the eukaryotic host. We show that the spirochetes can acquire cholesterol from plasma membranes of epithelial cells. In addition, through fluorescent and confocal microscopy combined with biochemical approaches, we demonstrated that B. burgdorferi labeled with the fluorescent cholesterol analog BODIPY-cholesterol or (3)H-labeled cholesterol transfer both cholesterol and cholesterol-glycolipids to HeLa cells. The transfer occurs through two different mechanisms, by direct contact between the bacteria and eukaryotic cell and/or through release of outer membrane vesicles. Thus, two-way lipid exchange between spirochetes and host cells can occur. This lipid exchange could be an important process that contributes to the pathogenesis of Lyme disease.
| S-EPMC3542181 | biostudies-literature
Project description:The host immune response to infection is a well-coordinated system of innate and adaptive immune cells working in concert to prevent the colonization and dissemination of a pathogen. While this typically leads to a beneficial outcome and the suppression of disease pathogenesis, the Lyme borreliosis bacterium, Borrelia burgdorferi sensu lato, can elicit an immune profile that leads to a deleterious state. As B. burgdorferi s.l. produces no known toxins, it is suggested that the immune and inflammatory response of the host are responsible for the manifestation of symptoms, including flu-like symptoms, musculoskeletal pain, and cognitive disorders. The past several years has seen a substantial increase in the use of microarray and sequencing technologies to investigate the transcriptome response induced by B. burgdorferi s.l., thus enabling researchers to identify key factors and pathways underlying the pathophysiology of Lyme borreliosis. In this review we present the major host transcriptional outcomes induced by the bacterium across several studies and discuss the overarching theme of the host inflammatory and immune response, and how it influences the pathology of Lyme borreliosis.
| S-EPMC8127729 | biostudies-literature
Project description:The transmission, survival, and virulence of Borrelia burgdorferi depend upon the spirochete's ability to modulate its transcriptome as it cycles between its arthropod vector and reservoir host. This complex adaptive process is collectively referred to as "host-adaptation." The paucibacillary nature of borrelial infections precludes the detailed analysis of host adaptation within infected mammalian tissues. To circumvent this limitation, we (J Clin Invest 101:2240-2250, 1998) developed a model system whereby spirochetes are cultivated within dialysis membrane chambers (DMCs) surgically implanted within the peritoneal cavity of a rat. Spirochetes within DMCs are exposed to many, if not all, of the environmental signals and physiological cues required for mammalian host adaptation but are protected from clearance by the host's immune system.
| S-EPMC5842696 | biostudies-literature
Project description:The Lyme disease spirochaete, Borrelia burgdorferi, can invade and persistently infect its hosts' connective tissues. We now demonstrate that B. burgdorferi adheres to the extracellular matrix component laminin. The surface-exposed outer-membrane protein ErpX was identified as having affinity for laminin, and is the first laminin-binding protein to be identified in a Lyme disease spirochaete. The adhesive domain of ErpX was shown to be contained within a small, unstructured hydrophilic segment at the protein's centre. The sequence of that domain is distinct from any previously identified bacterial laminin adhesin, suggesting a unique mode of laminin binding.
| S-EPMC10010501 | biostudies-literature
Project description:We have previously demonstrated that inhibition of autophagy increased the Borrelia burgdorferi induced innate cytokine production in vitro, but little is known regarding the effect of autophagy on in vivo models of Borrelia infection. Here, we showed that ATG7-deficient mice that were intra-articular injected with Borrelia spirochetes displayed increased joint swelling, cell influx, and enhanced interleukin-1β and interleukin-6 production by inflamed synovial tissue. Because both interleukin-1β and interleukin-6 are linked to the development of adaptive immune responses, we examine the function of autophagy on Borrelia induced adaptive immunity. Human peripheral blood mononuclear cells treated with autophagy inhibitors showed an increase in interleukin-17, interleukin-22, and interferon-γ production in response to exposure to Borrelia burgdorferi. Increased IL-17 production was dependent on IL-1β release but, interestingly, not on interleukin-23 production. In addition, cytokine quantitative trait loci in ATG9B modulate the Borrelia induced interleukin-17 production. Because high levels of IL-17 have been found in patients with confirmed, severe, chronic borreliosis, we propose that the modulation of autophagy may be a potential target for anti-inflammatory therapy in patients with persistent Lyme disease.
| S-EPMC6608026 | biostudies-literature