Rapid Clearance of Lyme Disease Spirochetes Lacking OspC from Skin

Tilly, Kit; Bestor, Aaron; Jewett, Mollie W.; Rosa, Patricia A.

doi:10.1128/iai.01725-06

Cited by 110 publications

(103 citation statements)

References 24 publications

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“…Repression of OspA/B expression in mammals is critical for the maintenance of the enzootic cycle because their expression would ultimately induce a strong humoral response and, as a result, may effectively block acquisition of B. burgdorferi by the vector [13][14][15], regardless of whether OspA/B can be targeted by borreliacidal antibodies in mammalian tissues [16]. B. burgdorferi abundantly expresses OspC only during early infection when the antigen has an important role and before specific humoral responses have developed [17][18][19]. OspC is not only a strong immunogen but also an effective target of protective immunity; its expression induces a robust humoral response that imposes tremendous pressure on the pathogen [20,21].…”

Section: Introductionmentioning

confidence: 99%

Verification and dissection of the ospC operator by using flaB promoter as a reporter in Borrelia burgdorferi

McShan

Liang

2008

Microbial Pathogenesis

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The Lyme disease spirochete Borrelia burgdorferi must repress expression of outer surface protein C (OspC) to effectively evade specific humoral immunity and to establish persistent infection. This ability largely relies upon a regulatory element, the only operator that has been reported in spirochetal bacteria. Immediately upstream of the ospC promoter, two sets of inverted repeats (IRs) constitute small and large palindromes, in which the right IR of the large palindrome contains the left IR of the small one, and may collectively function as the ospC operator. In the study, the large palindrome with or without the small IR was fused with a flaB promoter, which was used to drive expression of a promoterless ospC copy as a reporter gene, and introduced into OspC-deficient B. burgdorferi. The presence of the large palindrome alone significantly reduced ospC expression driven by the fused flaB promoter in the joint tissue of severe combined immunodeficiency (SCID) mice, and rescued spirochetes from elimination by passively transferred OspC antibody in infected SCID mice and specific immune responses elicited in immunocompetent mice, confirming a function of the IRs as an operator. Inclusion of the small IR further enhanced the ability of the large palindrome to reduce the activity of the fused flaB promoter, indicating that the small IR is a part of the operator. Taken together, the study led to successful verification and dissection of the ospC operator.

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Section: Introductionmentioning

confidence: 99%

Verification and dissection of the ospC operator by using flaB promoter as a reporter in Borrelia burgdorferi

McShan

Liang

2008

Microbial Pathogenesis

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“…The incorporation of OspC on its outer membrane prepares B. burgdorferi for transmission to a mammalian host, where it establishes persistent infection. We previously demonstrated that B. burgdorferi mutants lacking functional OspC cannot initiate mammalian infection following transmission by infected ticks (26,48,50,52). However, since OspC represents a potent neutralizing target, ospC expression must be downregulated after initiation of infection to avoid clearance of the spirochete by the host's acquired immune response (33)(34)(35)57).…”

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confidence: 99%

Regulation of the Virulence Determinant OspC by bbd18 on Linear Plasmid lp17 of Borrelia burgdorferi

et al. 2011

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Persistent infection of a mammalian host by Borrelia burgdorferi, the spirochete that causes Lyme disease, requires specific downregulation of an immunogenic outer surface protein, OspC. Although OspC is an essential virulence factor needed by the spirochete to establish infection in the mammal, it represents a potent target for the host acquired immune response, and constitutive expression of OspC results in spirochete clearance. In this study, we demonstrate that a factor encoded on a linear plasmid of B. burgdorferi, lp17, can negatively regulate ospC transcription from the endogenous gene on the circular plasmid cp26 and from an ospC promoter-lacZ fusion on a shuttle vector. Furthermore, we have identified bbd18 as the gene on lp17 that is responsible for this effect. These data identify a novel component of ospC regulation and provide the basis for determining the molecular mechanisms of ospC repression in vivo.

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“…Once activated, Rrp2ϳP acts as a transcriptional activator for the alternate sigma factor RpoN (6,87), which in turn controls expression of the spirochete's other alternate sigma factor, RpoS (7,20,36,52,70). Genes within the Rrp2/ RpoN/RpoS regulon promote tick-to-mammal transmission (30) and early murine infection (10,20,32,68,80,83).…”

mentioning

confidence: 99%

The Hybrid Histidine Kinase Hk1 Is Part of a Two-Component System That Is Essential for Survival of Borrelia burgdorferi in Feeding Ixodes scapularis Ticks

et al. 2011

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Two-component systems (TCS) are principal mechanisms by which bacteria adapt to their surroundings.Borrelia burgdorferi encodes only two TCS. One is comprised of a histidine kinase, Hk2, and the response regulator Rrp2. While the contribution of Hk2 remains unclear, Rrp2 is part of a regulatory pathway involving the spirochete's alternate sigma factors, RpoN and RpoS. Genes within the Rrp2/RpoN/RpoS regulon function to promote tick transmission and early infection. The other TCS consists of a hybrid histidine kinase, Hk1, and the response regulator Rrp1. Hk1 is composed of two periplasmic sensor domains (D1 and D2), followed by conserved cytoplasmic histidine kinase core, REC, and Hpt domains. In addition to its REC domain, Rrp1 contains a GGDEF motif characteristic of diguanylate cyclases. To investigate the role of Hk1 during the enzootic cycle, we inactivated this gene in two virulent backgrounds. Extensive characterization of the resulting mutants revealed a dramatic phenotype whereby Hk1-deficient spirochetes are virulent in mice and able to migrate out of the bite site during feeding but are killed within the midgut following acquisition. We hypothesize that the phosphorelay between Hk1 and Rrp1 is initiated by the binding of feeding-specific ligand(s) to Hk1 sensor domain D1 and/or D2. Once activated, Rrp1 directs the synthesis of cyclic dimeric GMP (c-di-GMP), which, in turn, modulates the expression and/or activity of gene products required for survival within feeding ticks. In contrast to the Rrp2/RpoN/RpoS pathway, which is active only within feeding nymphs, the Hk1/Rrp1 TCS is essential for survival during both larval and nymphal blood meals.

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Rapid Clearance of Lyme Disease Spirochetes Lacking OspC from Skin

Cited by 110 publications

References 24 publications

Verification and dissection of the ospC operator by using flaB promoter as a reporter in Borrelia burgdorferi

Verification and dissection of the ospC operator by using flaB promoter as a reporter in Borrelia burgdorferi

Regulation of the Virulence Determinant OspC by bbd18 on Linear Plasmid lp17 of Borrelia burgdorferi

The Hybrid Histidine Kinase Hk1 Is Part of a Two-Component System That Is Essential for Survival of Borrelia burgdorferi in Feeding Ixodes scapularis Ticks

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