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Borrelia burgdorferi oxidative stress regulator BosR directly represses lipoproteins primarily expressed in the tick during mammalian infection.

ABSTRACT: Differential gene expression is a key strategy adopted by the Lyme disease spirochaete, Borrelia burgdorferi, for adaptation and survival in the mammalian host and the tick vector. Many B.?burgdorferi surface lipoproteins fall into two distinct groups according to their expression patterns: one group primarily expressed in the tick and the other group primarily expressed in the mammal. Here, we show that the Fur homologue in this bacterium, also known as Borrelia oxidative stress regulator (BosR), is required for repression of outer surface protein A (OspA) and OspD in the mammal. Furthermore, BosR binds directly to sequences upstream of the ospAB operon and the ospD gene through recognition of palindromic motifs similar to those recognized by other Fur homologues but with a 1?bp variation in the spacer length. Putative BosR binding sites have been identified upstream of 156 B.?burgdorferi genes. Some of these genes share the same expression pattern as ospA and ospD. Most notably, 12 (67%) of the 18 genes previously identified in a genome-wide microarray study to be most significantly repressed in the mammal are among the putative BosR regulon. These data indicate that BosR may directly repress transcription of many genes that are downregulated in the mammal.

SUBMITTER: Wang P

PROVIDER: S-EPMC3772987 | biostudies-literature | 2013 Sep

REPOSITORIES: biostudies-literature

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Borrelia burgdorferi oxidative stress regulator BosR directly represses lipoproteins primarily expressed in the tick during mammalian infection.

Wang Peng P Dadhwal Poonam P Cheng Zhihui Z Zianni Michael R MR Rikihisa Yasuko Y Liang Fang Ting FT Li Xin X

Molecular microbiology 20130814 6

Differential gene expression is a key strategy adopted by the Lyme disease spirochaete, Borrelia burgdorferi, for adaptation and survival in the mammalian host and the tick vector. Many B. burgdorferi surface lipoproteins fall into two distinct groups according to their expression patterns: one group primarily expressed in the tick and the other group primarily expressed in the mammal. Here, we show that the Fur homologue in this bacterium, also known as Borrelia oxidative stress regulator (BosR ...[more]

PMID: 23869590

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Project description:Although BBA74 initially was described as a 28-kDa virulence-associated outer-membrane-spanning protein with porin-like function, subsequent studies revealed that it is periplasmic and downregulated in mammalian host-adapted spirochetes. To further elucidate the role of this protein in the Borrelia burgdorferi tick-mammal cycle, we conducted a thorough examination of its expression profile in comparison with the profiles of three well-characterized, differentially expressed borrelial genes (ospA, ospC, and ospE) and their proteins. In vitro, transcripts for bba74 were expressed at 23 degrees C and further enhanced by a temperature shift (37 degrees C), whereas BBA74 protein diminished at elevated temperatures; in contrast, neither transcript nor protein was expressed by spirochetes grown in dialysis membrane chambers (DMCs). Primer extension of wild-type B. burgdorferi grown in vitro, in conjunction with expression analysis of DMC-cultivated wild-type and rpoS mutant spirochetes, revealed that, like ospA, bba74 is transcribed by sigma(70) and is subject to RpoS-mediated repression within the mammalian host. A series of experiments utilizing wild-type and rpoS mutant spirochetes was conducted to determine the transcriptional and translational profiles of bba74 during the tick-mouse cycle. Results from these studies revealed (i) that bba74 is transcribed by sigma(70) exclusively during the larval and nymphal blood meals and (ii) that transcription of bba74 is bracketed by RpoS-independent and -dependent forms of repression that are induced by arthropod- and mammalian host-specific signals, respectively. Although loss of BBA74 does not impair the ability of B. burgdorferi to complete its infectious life cycle, the temporal compartmentalization of this gene's transcription suggests that BBA74 facilitates fitness of the spirochete within a narrow window of its tick phase. A reexamination of the paradigm for reciprocal regulation of ospA and ospC, performed herein, revealed that the heterogeneous expression of OspA and OspC displayed by spirochete populations during the nymphal blood meal results from the intricate sequence of transcriptional and translational changes that ensue as B. burgdorferi transitions between its arthropod vector and mammalian host.

Project description:The ferric uptake regulator (Fur) family of DNA-binding proteins represses and/or activates gene transcription via divalent metal ion-dependent signal sensing. The Borrelia burgdorferi Fur homologue, also known as Borrelia oxidative stress regulator (BosR), promotes spirochetal adaptation to the mammalian host by directly repressing the lipoproteins required for tick colonization and indirectly activating those required for establishing infection in the mammal. Here, we examined whether the DNA-binding activity of BosR was regulated by any of the four most prevalent transition metal ions in B. burgdorferi, Mn, Fe, Cu, and Zn. Our data indicated that in addition to a structural site occupied by Zn(II), BosR had two regulatory sites that could be occupied by Zn(II), Fe(II), or Cu(II) but not by Mn(II). While Fe(II) had no effect, Cu(II) and Zn(II) had a dose-dependent inhibitory effect on the BosR DNA-binding activity. Competition experiments indicated that Cu(II) had a higher affinity for BosR than Zn(II) or Fe(II). A BosR deficiency in B. burgdorferi resulted in a significant increase in the Cu level but no significant change in the levels of Mn, Fe, or Zn. These data suggest that Cu regulates BosR activity, and BosR in turn regulates Cu homeostasis in B. burgdorferi While this regulatory paradigm is characteristic of the Fur family, BosR is the first one shown to be responsive to Cu(II), which may be an adaptation to the potentially high level of Cu present in the Lyme disease spirochete.IMPORTANCE Transition metal ions serve an essential role in the metabolism of all living organisms. Members of the ferric uptake regulator (Fur) family play critical roles in regulating the cellular homeostasis of transition metals in diverse bacteria, and their DNA-binding activity is often regulated by coordination of the cognate divalent metal ions. To date, regulators with metal ion specificity to Fe(II), Mn(II), Zn(II), and Ni(II) have all been described. In this study, we demonstrate that BosR, the sole Fur homologue in Borrelia burgdorferi, is responsive to Cu(II) and regulates Cu homeostasis in this bacterium, which may be an adaption to potentially Cu-rich milieu in the Lyme disease spirochete. This study has expanded the repertoire of the Fur family's metal ion specificity.

Dataset Information

Borrelia burgdorferi oxidative stress regulator BosR directly represses lipoproteins primarily expressed in the tick during mammalian infection.

Publications

Borrelia burgdorferi oxidative stress regulator BosR directly represses lipoproteins primarily expressed in the tick during mammalian infection.

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