Survival strategies of Borrelia burgdorferi, the etiologic agent of Lyme disease

Embers, Monica E.; Ramamoorthy, Ramesh; Philipp, Mario T.

doi:10.1016/j.micinf.2003.11.014

Cited by 74 publications

(67 citation statements)

References 65 publications

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“…The genome of B. burgdorferi encodes a limited set of known regulators of gene expression (33). Therefore, it is conceivable that a network of multiple regulators may contribute to the fine-tuning of the signal-dependent adaptive gene expression in B. burgdorferi that facilitates transmission and colonization between hosts with highly disparate microenvironments (10,11,18,28,33,44,55,68,80).…”

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confidence: 99%

CsrA Modulates Levels of Lipoproteins and Key Regulators of Gene Expression Critical for Pathogenic Mechanisms of Borrelia burgdorferi

et al. 2011

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Carbon storage regulator A (CsrA) is an RNA binding protein that has been characterized in many bacterial species to play a central regulatory role by modulating several metabolic processes. We recently showed that a homolog of CsrA in Borrelia burgdorferi (CsrA Bb , BB0184) was upregulated in response to propagation of B. burgdorferi under mammalian host-specific conditions. In order to further delineate the role of CsrA Bb , we generated a deletion mutant designated ES10 in a linear plasmid 25-negative isolate of B. burgdorferi strain B31 (ML23). The deletion mutant was screened by PCR and Southern blot hybridization, and a lack of synthesis of CsrA Bb in ES10 was confirmed by immunoblot analysis. Analysis of ES10 propagated at pH 6.8/37°C revealed a significant reduction in the levels of OspC, DbpA, BBK32, and BBA64 compared to those for the parental wild-type strain propagated under these conditions, while there were no significant changes in the levels of either OspA or P66. Moreover, the levels of two regulatory proteins, RpoS and BosR, were also found to be lower in ES10 than in the control strain. Quantitative real-time reverse transcription-PCR analysis of total RNA extracted from the parental strain and csrA Bb mutant revealed significant differences in gene expression consistent with the changes at the protein level. Neither the csrA Bb mutant nor the trans-complemented strain was capable of infection following intradermal needle inoculation in C3H/HeN mice at either 10 3 or 10 5 spirochetes per mouse. The further characterization of molecular basis of regulation mediated by CsrA Bb will provide significant insights into the pathophysiology of B. burgdorferi.

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CsrA Modulates Levels of Lipoproteins and Key Regulators of Gene Expression Critical for Pathogenic Mechanisms of Borrelia burgdorferi

et al. 2011

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“…There also is an extensive body of evidence implicating this bacterium's abundant lipid-modified proteins, which signal via CD14 and/or Toll-like receptor 2 (TLR2)/TLR1 heterodimers (3,7,9,18,50,60,100,105,106,123), as major proinflammatory agonists during infection. Recognition that the host needs to protect itself against uncontrolled inflammation has spawned interest in how LD spirochetes might down-modulate inflammatory processes; such studies have focused mainly on the ability of spirochetes and spirochetal products to induce the production of the anti-inflammatory cytokine interleukin-10 (IL-10) (19,36,42). Investigations of innate responses to bacterial pathogens have relied heavily upon the use of monocytic or transformed nonmyeloid cell lines in conjunction with isolated or synthetic microbial molecular patterns (3).…”

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Phagocytosis ofBorrelia burgdorferi, the Lyme Disease Spirochete, Potentiates Innate Immune Activation and Induces Apoptosis in Human Monocytes

Cruz¹,

Moore²,

Vake³

et al. 2008

Infect Immun

106

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We have previously demonstrated that phagocytosed Borrelia burgdorferi induces activation programs in human peripheral blood mononuclear cells that differ qualitatively and quantitatively from those evoked by equivalent lipoprotein-rich lysates. Here we report that ingested B. burgdorferi induces significantly greater transcription of proinflammatory cytokine genes than do lysates and that live B. burgdorferi, but not B. burgdorferi lysate, is avidly internalized by monocytes, where the bacteria are completely degraded within phagolysosomes. In the course of these experiments, we discovered that live B. burgdorferi also induced a dose-dependent decrease in monocytes but not a decrease in dendritic cells or T cells and that the monocyte population displayed morphological and biochemical hallmarks of apoptosis. Particularly noteworthy was the finding that apoptotic changes occurred predominantly in monocytes that had internalized spirochetes. Abrogation of phagocytosis with cytochalasin D prevented the death response. Heat-killed B. burgdorferi, which was internalized as well as live organisms, induced a similar degree of apoptosis of monocytes but markedly less cytokine production. Surprisingly, opsonophagocytosis of Treponema pallidum did not elicit a discernible cell death response. Our combined results demonstrate that B. burgdorferi confined to phagolysosomes is a potent inducer of cytosolic signals that result in (i) production of NF-B-dependent cytokines, (ii) assembly of the inflammasome and activation of caspase-1, and (iii) induction of programmed cell death. We propose that inflammation and apoptosis represent mutually reinforcing components of the immunologic arsenal that the host mobilizes to defend itself against infection with Lyme disease spirochetes.

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“…The intermittent inflammatory reactions and remission phases might reflect an immune response against different Bb variants. Bb has the ability to modulate the expression of its highly immunogenic outer surface proteins (31). It is possible that in an environment where immunoregulatory mechanisms are compromised, expression of Bb variants might flare up the host immune response.…”

Section: Discussionmentioning

confidence: 99%

CD28 Deficiency Exacerbates Joint Inflammation upon Borrelia burgdorferi Infection, Resulting in the Development of Chronic Lyme Arthritis

Iliopoulou¹,

Alroy

Huber³

2007

The Journal of Immunology

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Lyme disease, caused by the tick-borne spirochete Borrelia burgdorferi (Bb), is a multisystem illness, affecting many organs, such as the heart, the nervous system, and the joints. Months after Bb infection, ∼60% of patients experience intermittent arthritic attacks, a condition that in some individuals progresses to chronic joint inflammation. Although mice develop acute arthritis in response to Bb infection, the joint inflammation clears after 2 wk, despite continuous infection, only very rarely presenting with chronic Lyme arthritis. Thus, the lack of an animal system has so far prevented the elucidation of this persistent inflammatory process that occurs in humans. In this study, we report that the majority of Bb-infected CD28−/− mice develop chronic Lyme arthritis. Consistent with observations in chronic Lyme arthritis patients, the infected mutant, but not wild-type mice present recurring monoarticular arthritis over an extended time period, as well as anti-outer surface protein A of Bb serum titers. Furthermore, we demonstrate that anti-outer surface protein A Abs develop in these mice only after establishment of chronic Lyme arthritis. Thus, the Bb-infected CD28−/− mice provide a murine model for studying chronic Lyme arthritis.

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Survival strategies of Borrelia burgdorferi, the etiologic agent of Lyme disease

Cited by 74 publications

References 65 publications

CsrA Modulates Levels of Lipoproteins and Key Regulators of Gene Expression Critical for Pathogenic Mechanisms of Borrelia burgdorferi

CsrA Modulates Levels of Lipoproteins and Key Regulators of Gene Expression Critical for Pathogenic Mechanisms of Borrelia burgdorferi

Phagocytosis ofBorrelia burgdorferi, the Lyme Disease Spirochete, Potentiates Innate Immune Activation and Induces Apoptosis in Human Monocytes

CD28 Deficiency Exacerbates Joint Inflammation upon Borrelia burgdorferi Infection, Resulting in the Development of Chronic Lyme Arthritis

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