Adaptation of<i>Borrelia burgdorferi</i>in the tick and the mammalian host

Anguíta, Juan; Hedrick, Michael N.; Fikrig, Erol

doi:10.1016/s0168-6445(03)00036-6

Cited by 71 publications

(53 citation statements)

References 120 publications

(158 reference statements)

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“…These IRs are highly conserved among ospC homologs of many B. burgdorferi strains (29,55) and have been hypothesized to be involved in ospC regulation (1,55). To assess the potential role(s) of the IRs in ospC expression, we first generated complementation constructs lacking either IR 1 or both IR 1 and IR 2 (Fig. 3A).…”

Section: Resultsmentioning

confidence: 99%

Analysis of theospCRegulatory Element Controlled by the RpoN-RpoS Regulatory Pathway inBorrelia burgdorferi

et al. 2005

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Outer surface lipoprotein C (OspC) is a key virulence factor of Borrelia burgdorferi. ospC is differentially regulated during borrelial transmission from ticks to rodents, and such regulation is essential for maintaining the spirochete in its natural enzootic cycle. Recently, we showed that the expression of ospC in B. burgdorferi is governed by a novel alternative sigma factor regulatory network, the RpoN-RpoS pathway. However, the precise mechanism by which the RpoN-RpoS pathway controls ospC expression has been unclear. In particular, there has been uncertainty regarding whether ospC is controlled directly by RpoS ( s ) or indirectly through a transactivator (induced by RpoS). Using deletion analyses and genetic complementation in an OspC-deficient mutant of B. burgdorferi, we analyzed the cis element(s) required for the expression of ospC in its native borrelial background. Two highly conserved upstream inverted repeat elements, previously implicated in ospC regulation, were not required for ospC expression in B. burgdorferi. Using similar approaches, a minimal promoter that contained a canonical ؊35/؊10 sequence necessary and sufficient for s -dependent regulation of ospC was identified. Further, targeted mutagenesis of a C at position ؊15 within the extended ؊10 region of ospC, which is postulated to function like the strategic C residue important for E s binding in Escherichia coli, abolished ospC expression. The minimal ospC promoter also was responsive to coumermycin A 1 , further supporting its s character. The combined data constitute a body of evidence that the RpoN-RpoS regulatory network controls ospC expression by direct binding of s to a s -dependent promoter of ospC. The implication of our findings to understanding how B. burgdorferi differentially regulates ospC and other ospC-like genes via the RpoN-RpoS regulatory pathway is discussed.

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Section: Resultsmentioning

confidence: 99%

Analysis of theospCRegulatory Element Controlled by the RpoN-RpoS Regulatory Pathway inBorrelia burgdorferi

et al. 2005

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“…B. burgdorferi persistently colonizes the gut of ticks. When infected ticks feed, the spirochetes multiply within the gut, migrate to the tick's salivary glands, and infect the vertebrate host (1). Within the feeding tick, the spirochetes alter the expression of many genes in preparation for transmission and infection of the new host (1,26).…”

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confidence: 99%

Reciprocal Expression of ospA and ospC in Single Cells of Borrelia burgdorferi

Srivastava

Silva

2008

J Bacteriol

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Outer surface proteins (Osp) A and C of the Lyme disease spirochete (Borrelia burgdorferi) are selectively produced and of functional significance in the tick vector and mammalian host, respectively. Some studies indicate a simple, reciprocal relationship where the signals and pathways that turn on ospC also turn off ospA. Other studies indicate a more complex regulation where many spirochetes produce both proteins and others produce one of the proteins or neither protein. Here, we have used flow cytometry to characterize ospA and ospC transcript and protein levels in individual bacterial cells grown in culture. The results support a simple, reciprocal model where, at the level of single cells, the transcription of ospC is linked to the repression of ospA. We also demonstrate that under conditions conducive for OspC production, spirochetes display an "all or none" response, with some cells displaying high levels of ospC transcription and others demonstrating little or no transcription. Despite the reciprocal regulation of ospA and ospC at the single-cell level, we propose that spirochetes display an array of phenotypes due to stochasticity in the pathways that regulate osp expression and the slow turnover of outer surface proteins.Borrelia burgdorferi, the spirochete responsible for Lyme disease, is transmitted by Ixodes ticks (3). B. burgdorferi persistently colonizes the gut of ticks. When infected ticks feed, the spirochetes multiply within the gut, migrate to the tick's salivary glands, and infect the vertebrate host (1). Within the feeding tick, the spirochetes alter the expression of many genes in preparation for transmission and infection of the new host (1, 26). B. burgdorferi outer surface proteins (Osp) A and C have served as a paradigm for understanding the regulation of bacterial gene expression within feeding ticks. In ticks, ospA is predominantly expressed before the blood meal, whereas ospC is induced during the blood meal (9,17,22,23). The functions of these two proteins are consistent with their pattern of expression, where OspA is required for colonizing the vector and OspC is required for infecting the host (12,19,29).Temperature, pH, and cell density act as signals for regulating the expression of ospA and -C in culture, and these signals are likely to play a role in the feeding tick as well (26). Proteomic and microarray studies with cultured spirochetes grown in "tick-like" (low temperature, high pH) or "host-like" (high temperature, low pH) conditions have led to the identification of large subsets of Borrelia proteins and genes with "OspAlike" or "OspC-like" patterns of expression (18,20). The bacterial signaling pathway regulating the expression of ospC and ospC-like genes has been characterized in some detail (6,7,14,24,27,28). The pathway is activated by a two-component system consisting of a sensor with a histidine kinase domain (HK2) and a cytoplasmic response regulator protein (Rrp2) (14, 27). Activated Rrp2, together with the alternative sigma factor RpoN, induces the expression of...

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“…Tick salivary proteins enter the host and exert pleiotropic immunosuppressive effects (3)(4)(5)(6)(7)(8)(9) that could also contribute to the efficient transmission of pathogens (10). I. scapularis salivary protein (Salp) 15 is a pleiotropic inducible Ag that may be responsible for the immunomodulatory action of tick saliva on acquired immune responses (3) and the protection of the causative agent of Lyme disease, B. burgdorferi, against Ab-mediated killing (11), which complements other immune evasion mechanisms by the spirochete (12). Inhibition of CD4 ϩ T cell activation mediated by Salp15 results from the repression of IL-2 production upon recognition of cognate Ag (3).…”

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confidence: 99%

Cutting Edge: CD4 Is the Receptor for the Tick Saliva Immunosuppressor, Salp15

Garg¹,

Juncadella

Ramamoorthi

et al. 2006

The Journal of Immunology

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112

127

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Salp15 is an Ixodes scapularis salivary protein that inhibits CD4+ T cell activation through the repression of TCR ligation-triggered calcium fluxes and IL-2 production. We show in this study that Salp15 binds specifically to the CD4 coreceptor on mammalian host T cells. Salp15 specifically associates through its C-terminal residues with the outermost two extracellular domains of CD4. Upon binding to CD4, Salp15 inhibits the subsequent TCR ligation-induced T cell signaling at the earliest steps including tyrosine phosphorylation of the Src kinase Lck, downstream effector proteins, and lipid raft reorganization. These results provide a molecular basis to understanding the immunosuppressive activity of Salp15 and its specificity for CD4+ T cells.

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Adaptation ofBorrelia burgdorferiin the tick and the mammalian host

Cited by 71 publications

References 120 publications

Analysis of theospCRegulatory Element Controlled by the RpoN-RpoS Regulatory Pathway inBorrelia burgdorferi

Analysis of theospCRegulatory Element Controlled by the RpoN-RpoS Regulatory Pathway inBorrelia burgdorferi

Reciprocal Expression of ospA and ospC in Single Cells of Borrelia burgdorferi

Cutting Edge: CD4 Is the Receptor for the Tick Saliva Immunosuppressor, Salp15

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