Regulation of Expression of the
            <i>Borrelia burgdorferi</i>
            β
            <sub>3</sub>
            -Chain Integrin Ligand, P66, in Ticks and in Culture

Cugini, Carla; Medrano, Melisa S.; Schwan, Tom G.; Coburn, Jenifer

doi:10.1128/iai.71.2.1001-1007.2003

Cited by 43 publications

(56 citation statements)

References 27 publications

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“…2B, ␣-P66, lanes 1, 2, and 3; all strains). These observations were consistent with those of a previous study where it was demonstrated that the levels of P66 were not affected by either temperature, pH, or a combination of these factors (14). The above analysis also suggests that the loss of expression of BBA64 did not affect other critical determinants which are known to play a role in the infectious process, albeit this analysis was limited to OspC and P66.…”

Section: Construction Of the Bba64 Mtsupporting

confidence: 82%

Role of the BBA64 Locus of Borrelia burgdorferi in Early Stages of Infectivity in a Murine Model of Lyme Disease

et al. 2008

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Borrelia burgdorferi, the causative agent of Lyme disease, undergoes rapid adaptive gene expression in response to environmental signals encountered during different stages of its life cycle in the arthropod vector or the mammalian host. Among all the plasmid-encoded genes of B. burgdorferi, several linear plasmid 54 (lp54)-encoded open reading frames (ORFs) exhibit the greatest differential expression in response to mammalian host-specific temperature, pH, and other uncharacterized signals. These ORFs include members of the paralogous gene family 54 (pgf 54), such as BBA64, BBA65, and BBA66, present on lp54. In an attempt to correlate transcriptional up-regulation of these pgf 54 members to their role in infectivity, we inactivated BBA64 and characterized the phenotype of this mutant both in vitro and in vivo. There were no major differences in the protein profiles between the BBA64 mutant and the control strains, while immunoblot analysis indicated that inactivation of BBA64 resulted in increased levels of BBA65. Moreover, there was no significant difference in the ability of the BBA64 mutant to infect C3H/HeN mice compared to that of its parental or complemented control strains as determined by culturing of viable spirochetes from infected tissues. However, enumeration of spirochetes using quantitative real-time PCR revealed tissue-specific differences, suggesting a minimal role for BBA64 in the survival of B. burgdorferi in select tissues. Infectivity analysis of the BBA64 mutant suggests that B. burgdorferi may utilize multiple determinants to establish infection in mammalian hosts.Lyme disease is the most prevalent arthropod-borne infection in the United States and remains a significant public health issue in certain geographic loci (3,46). It is a multiphasic disorder with clinical symptoms involving the cutaneous, musculoskeletal, cardiovascular, and nervous systems (62). Borrelia burgdorferi, the causative agent of Lyme disease, is transmitted to several vertebrate hosts, including humans, by the bite of infected Ixodes ticks. When ticks consume a blood meal from mammalian hosts, there is a rapid alteration of gene expression in B. burgdorferi, facilitating adaptation of the spirochetes to the highly disparate environmental conditions that exist between the tick vector and the vertebrate host (4, 9, 10, 15, 29, 30-32, 44, 53, 57-59, 63, 67). This adaptive gene expression may aid in the efficient trafficking of the spirochetes from the tick vector to the mammalian host and subsequently facilitate dissemination and colonization of various host tissues (16,22).Whole-genome transcriptional analyses using B. burgdorferi, propagated under in vitro growth conditions that mimic either the tick vector or mammalian host environment, have revealed preferential expression of plasmid-encoded genes (4,44,53,66). Among the several linear and circular plasmids present in B. burgdorferi, linear plasmid 54 (lp54) encodes the largest number of open reading frames (ORFs) that exhibit differential gene expression in respon...

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Section: Construction Of the Bba64 Mtsupporting

confidence: 82%

Role of the BBA64 Locus of Borrelia burgdorferi in Early Stages of Infectivity in a Murine Model of Lyme Disease

et al. 2008

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“…In contrast to invasin, a ␤ 1 integrin ligand of Yersinia pseudotuberculosis, P66 would not be expected to promote uptake of the bacteria by mammalian cells, as there is no current evidence that B. burgdorferi occupies an intracellular niche during mammalian infection. The significance of P66 is also predicted to be in the mammal rather than in the tick, as P66 is not produced by B. burgdorferi in unfed ticks but is expressed during mammalian infection and as the bacteria are acquired by, or transmitted by, the tick (14). P66 expression then correlates with factors specific to mammalian infection.…”

Section: Discussionmentioning

confidence: 96%

The Borrelia burgdorferi Integrin Ligand P66 Affects Gene Expression by Human Cells in Culture

et al. 2011

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Borrelia burgdorferi, an agent of Lyme disease, establishes persistent infection in immunocompetent animals and humans. Although the infection in humans can be cleared by antibiotic therapy, persistence in reservoir animals is necessary for the maintenance of the bacterium in the natural reservoir hostNtick vector infectious cycle. B. burgdorferi binds to ␤ 1 -and ␤ 3 -chain integrins, and the P66 outer membrane protein is responsible for at least some of the integrin binding activity of the spirochete. Because integrins are transmembrane, bidirectional signaling molecules, integrin binding may alter the nature of the host response to the bacteria. We used isogenic B. burgdorferi p66؉ and ⌬p66 strains to analyze the responses of cultured human cells to P66-integrin interaction during infection. Microarray results suggest that the response differs according to the cell type, infection time, and experimental conditions. Clusters of genes in functionally related categories that showed significant changes included proteins involved in cell-extracellular matrix interactions, actin dynamics, stress response, and immune responses. Integrin binding by P66 may therefore help B. burgdorferi establish infection by facilitating tissue invasion and modulating the activation of the immune system to other components of the bacteria, e.g., lipoproteins. These results provide insight into how B. burgdorferi is able to establish infection in immunocompetent hosts.

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“…Gene regulation during the tick phase of the enzootic cycle has come to be recognized as equally important to the spirochete's survival strategy (24,29,32,53,67,73,74,91,92,96). In this regard, recent evidence obtained from expression profiling of p66 and ospD points to the existence of arthropod-specific signals that modulate B. burgdorferi gene expression at various times during the tick phases of the cycle (24,91).…”

mentioning

confidence: 99%

“…It also is now evident, however, that spirochetes must be exposed to as yet unidentified mammalian host-specific signals to induce the full range of transcriptional and translational changes that occur during infection (1,13,17,19,39,97). Gene regulation during the tick phase of the enzootic cycle has come to be recognized as equally important to the spirochete's survival strategy (24,29,32,53,67,73,74,91,92,96). In this regard, recent evidence obtained from expression profiling of p66 and ospD points to the existence of arthropod-specific signals that modulate B. burgdorferi gene expression at various times during the tick phases of the cycle (24,91).…”

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confidence: 99%

Borrelia burgdorferi bba74Is Expressed Exclusively during Tick Feeding and Is Regulated by Both Arthropod- and Mammalian Host-Specific Signals

Mulay¹,

Caimano²,

Iyer

et al. 2009

J Bacteriol

117

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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°C and further enhanced by a temperature shift (37°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 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 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.Lyme disease, the most common arthropod-borne infection in the United States, is caused by the spirochete Borrelia burgdorferi (87). In nature, B. burgdorferi has an obligate biannual enzootic cycle involving small mammalian host reservoirs, typically Peromyscus leucopus, and an Ixodes tick vector (51, 96). To successfully complete this life cycle, B. burgdorferi must adapt to and propagate within two markedly different physiologic milieus (67,75,96). A number of investigators have reported that manipulation of parameters, such as temperature, pH, DNA supercoiling, cell density, and partial O 2 pressure, during in vitro cultivation can trigger changes in gene and protein expression resembling those that occur when spirochetes adapt to their mammalian host (4,20,21,44,45,65,74,77,78,89,102). It als...

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Regulation of Expression of the Borrelia burgdorferi β ₃ -Chain Integrin Ligand, P66, in Ticks and in Culture

Cited by 43 publications

References 27 publications

Role of the BBA64 Locus of Borrelia burgdorferi in Early Stages of Infectivity in a Murine Model of Lyme Disease

Role of the BBA64 Locus of Borrelia burgdorferi in Early Stages of Infectivity in a Murine Model of Lyme Disease

The Borrelia burgdorferi Integrin Ligand P66 Affects Gene Expression by Human Cells in Culture

Borrelia burgdorferi bba74Is Expressed Exclusively during Tick Feeding and Is Regulated by Both Arthropod- and Mammalian Host-Specific Signals

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Regulation of Expression of the Borrelia burgdorferi β 3 -Chain Integrin Ligand, P66, in Ticks and in Culture

Cited by 43 publications

References 27 publications

Role of the BBA64 Locus of Borrelia burgdorferi in Early Stages of Infectivity in a Murine Model of Lyme Disease

Role of the BBA64 Locus of Borrelia burgdorferi in Early Stages of Infectivity in a Murine Model of Lyme Disease

The Borrelia burgdorferi Integrin Ligand P66 Affects Gene Expression by Human Cells in Culture

Borrelia burgdorferi bba74Is Expressed Exclusively during Tick Feeding and Is Regulated by Both Arthropod- and Mammalian Host-Specific Signals

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Regulation of Expression of the Borrelia burgdorferi β ₃ -Chain Integrin Ligand, P66, in Ticks and in Culture