<i>Borrelia burgdorferi bba66</i>
            Gene Inactivation Results in Attenuated Mouse Infection by Tick Transmission

Patton, Toni G.; Brandt, Kevin S.; Nolder, Christi; Clifton, Dawn R.; Carroll, James A.; Gilmore, Robert D.

doi:10.1128/iai.00140-13

Cited by 32 publications

(36 citation statements)

References 55 publications

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“…2a). Notably, asRNAs were identified opposite to key genes active in the maintenance of the B. burgdorferi life cycle and cell division, such as: bb0420 ( hk1 ), bb0827 ( hrpA ), bbb03 ( resT ), bbb17 ( guaB ), and bba66 [4, 13, 44–50]. Hk1 is the histidine kinase in the two-component system necessary for B. burgdorferi survival in the tick [45].…”

Section: Resultsmentioning

confidence: 99%

Temperature-dependent sRNA transcriptome of the Lyme disease spirochete

et al. 2017

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BackgroundTransmission of Borrelia burgdorferi from its tick vector to a vertebrate host requires extensive reprogramming of gene expression. Small regulatory RNAs (sRNA) have emerged in the last decade as important regulators of bacterial gene expression. Despite the widespread observation of sRNA-mediated gene regulation, only one sRNA has been characterized in the Lyme disease spirochete B. burgdorferi. We employed an sRNA-specific deep-sequencing approach to identify the small RNA transcriptome of B. burgdorferi at both 23 °C and 37 °C, which mimics in vitro the transmission from the tick vector to the mammalian host.ResultsWe identified over 1000 sRNAs in B. burgdorferi revealing large amounts of antisense and intragenic sRNAs, as well as characteristic intergenic and 5′ UTR-associated sRNAs. A large fraction of the novel sRNAs (43%) are temperature-dependent and differentially expressed at the two temperatures, suggesting a role in gene regulation for adaptation during transmission. In addition, many genes important for maintenance of Borrelia during its enzootic cycle are associated with antisense RNAs or 5′ UTR sRNAs. RNA-seq data were validated for twenty-two of the sRNAs via Northern blot analyses.ConclusionsOur study demonstrates that sRNAs are abundant and differentially expressed by environmental conditions suggesting that gene regulation via sRNAs is a common mechanism utilized in B. burgdorferi. In addition, the identification of antisense and intragenic sRNAs impacts the broadly used loss-of-function genetic approach used to study gene function and increases the coding potential of a small genome. To facilitate access to the analyzed RNA-seq data we have set-up a website at http://www.cibiv.at/~niko/bbdb/ that includes a UCSC browser track hub. By clicking on the respective link, researchers can interactively inspect the data in the UCSC genome browser (Kent et al., Genome Res 12:996-1006, 2002).Electronic supplementary materialThe online version of this article (doi:10.1186/s12864-016-3398-3) contains supplementary material, which is available to authorized users.

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Section: Resultsmentioning

confidence: 99%

Temperature-dependent sRNA transcriptome of the Lyme disease spirochete

et al. 2017

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“…Together, these data have enabled us to extend our conceptualization of RpoS's gatekeeper function. At the onset of transmission, the synthesis of RpoS induces the tightly coordinated expression of genes required for physiological adaptation to the blood meal (i.e., cdr) (117), network formation (i.e., bba64) (118,119), chemotactic migration out of the midgut (i.e., mcp-4 and mcp-5), and early mammalian infection (i.e., ospC and dbpBA) (19,66,108). Collectively, we liken the RpoS-on state to a Go signal for tick-to-mammal transmission (19).…”

Section: Discussionmentioning

confidence: 99%

Cyclic di-GMP Modulates Gene Expression in Lyme Disease Spirochetes at the Tick-Mammal Interface To Promote Spirochete Survival during the Blood Meal and Tick-to-Mammal Transmission

et al. 2015

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e Borrelia burgdorferi, the Lyme disease spirochete, couples environmental sensing and gene regulation primarily via the Hk1/ Rrp1 two-component system (TCS) and Rrp2/RpoN/RpoS pathways. Beginning with acquisition, we reevaluated the contribution of these pathways to spirochete survival and gene regulation throughout the enzootic cycle. Live imaging of B. burgdorferi caught in the act of being acquired revealed that the absence of RpoS and the consequent derepression of tick-phase genes impart a Stay signal required for midgut colonization. In addition to the behavioral changes brought on by the RpoS-off state, acquisition requires activation of cyclic di-GMP (c-di-GMP) synthesis by the Hk1/Rrp1 TCS; B. burgdorferi lacking either component is destroyed during the blood meal. Prior studies attributed this dramatic phenotype to a metabolic lesion stemming from reduced glycerol uptake and utilization. In a head-to-head comparison, however, the B. burgdorferi ⌬glp mutant had a markedly greater capacity to survive tick feeding than B. burgdorferi ⌬hk1 or ⌬rrp1 mutants, establishing unequivocally that glycerol metabolism is only one component of the protection afforded by c-di-GMP. Data presented herein suggest that the protective response mediated by c-di-GMP is multifactorial, involving chemotactic responses, utilization of alternate substrates for energy generation and intermediary metabolism, and remodeling of the cell envelope as a means of defending spirochetes against threats engendered during the blood meal. Expression profiling of c-di-GMP-regulated genes through the enzootic cycle supports our contention that the Hk1/Rrp1 TCS functions primarily, if not exclusively, in ticks. These data also raise the possibility that c-di-GMP enhances the expression of a subset of RpoS-dependent genes during nymphal transmission. Borrelia burgdorferi, the causative agent of Lyme disease, is maintained in nature within an enzootic cycle that involves an arthropod vector and vertebrate reservoir hosts, typically, small rodents and birds (1). In the northeastern United States, the primary vector for B. burgdorferi is the black-legged deer tick, Ixodes scapularis (2, 3). Because B. burgdorferi cannot be passaged transovarially, naive larvae acquire spirochetes by feeding on infected reservoir hosts. Successful colonization of the vector requires B. burgdorferi to establish an intimate association with rapidly differentiating, highly endocytic midgut epithelial cells (4-6). In order to accomplish this feat, spirochetes must resist deleterious substances within the midgut lumen, such as host-and tick-derived innate immune effector molecules, reactive oxygen species (ROS), and salivary enzymes imbibed from the feeding site (4, 7-11). At the same time, B. burgdorferi also must alter its metabolic machinery to exploit the availability of alternative carbon sources (e.g., glycerol, N-acetylglucosamine [GlcNAc], chitobiose) as the supply of ingested glucose diminishes (12-15). During nymphal transmission, spirochetes are almost certai...

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“…"Endemic" and "nonendemic" refer to samples from patients in areas where Lyme disease is and is not endemic, respectively. Lyme disease Early Lyme disease with EM Acute phase (23) 14 (61) 9 (40) 2 (9) 7 (30) 7 (30) 1 (4) 7 (30) 5 (22) 6 (26) 2 (9) 4 (17) 5 (22) 6 (26) 5 (22) 1 (4) 5 (22) Convalescent phase (23) 22 (96) 16 (70) 6 (26) 16 (70) 18 (78) 7 (30) 9 (39) 8 (35) 11 (48) 2 (9) 6 (26) 10 (43) 15 (65) 8 (35) 1 (4) 6 (26) Lyme neuroborreliosis (10) 9 (90) 10 (100) 3 (30) 9 (90) 9 (90) 4 (40) 7 (70) 3 (30) 5 (50) 2 (20) 3 (30) 5 (50) 7 (70) 6 (60) 1 (10) 2 (20) Lyme carditis (6) 6 (100) 3 (50) 5 (83) 4 (67) 5 (83) 3 (50)<...>…”

Section: Discussionmentioning

confidence: 99%

“…The genes encode surface-localized membrane lipoproteins that elicit antibody responses in humans and experimental animals following B. burgdorferi infection (11,(17)(18)(19). Functional aspects of the genes and their encoded products have been investigated, with the findings that BBA64 and BBA66 are involved in B. burgdorferi transmission from ticks (13,20); BBA68 is designated a complement regulator-acquiring surface protein (CRASP) that plays a role in the inactivation of complement (21,22), and BBA70 has recently been described as a plasminogen-binding protein (23). Historically, these genes have been characterized as paralogs and were originally annotated as belonging to one of several paralogous gene families (pgf54 or PFam 54) in the B. burgdorferi genome (10,24,25).…”

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confidence: 99%

Evaluation of Selected Borrelia burgdorferi lp54 Plasmid-Encoded Gene Products Expressed during Mammalian Infection as Antigens To Improve Serodiagnostic Testing for Early Lyme Disease

Weiner

Crew

Brandt

et al. 2015

Clin Vaccine Immunol

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Laboratory testing for the diagnosis of Lyme disease is performed primarily by serologic assays and is accurate for detection beyond the acute stage of the infection. Serodiagnostic assays to detect the early stages of infection, however, are limited in their sensitivity, and improvement is warranted. We analyzed a series of Borrelia burgdorferi proteins known to be induced within feeding ticks and/or during mammalian infection for their utility as serodiagnostic markers against a comprehensive panel of Lyme disease patient serum samples. The antigens were assayed for IgM and IgG reactivity in line immunoblots and separately by enzyme-linked immunosorbent assay (ELISA), with a focus on reactivity against early Lyme disease with erythema migrans (EM), early disseminated Lyme neuroborreliosis, and early Lyme carditis patient serum samples. By IgM immunoblotting, we found that recombinant proteins BBA65, BBA70, and BBA73 reacted with early Lyme EM samples at levels comparable to those of the OspC antigen used in the current IgM blotting criteria. Additionally, these proteins reacted with serum samples from patients with early neuroborreliosis and early carditis, suggesting value in detecting early stages of this disease progression. We also found serological reactivity against recombinant proteins BBA69 and BBA73 with early-Lyme-disease samples using IgG immunoblotting and ELISA. Significantly, some samples that had been scored negative by the Centers for Disease Control and Prevention-recommended 2-tiered testing algorithm demonstrated positive reactivity to one or more of the antigens by IgM/IgG immunoblot and ELISA. These results suggest that incorporating additional in vivo-expressed antigens into the current IgM/IgG immunoblotting tier in a recombinant protein platform assay may improve the performance of early-Lyme-disease serologic testing.A ccurate diagnoses are essential to treat patients with Lyme disease, a tick-borne illness caused by the bacterial agent Borrelia burgdorferi. Diagnosis in the initial stages of Lyme disease can be made by clinical signs such as the onset of flu-like symptoms with the presence of a rash termed erythema migrans (EM) at the site of the tick bite (1, 2). Aiding the diagnostic evaluation, Lyme disease in the United States is endemic and transmitted by the tick vectors Ixodes scapularis in the Northeast and upper Midwest, and Ixodes pacificus in parts of the Pacific Northwest (http://www.cdc .gov/lyme/stats/index.html). However, it is not always apparent that a patient was bitten by an infected tick, and the EM may not appear or may go unnoticed, leading to a disseminated infection with more severe clinical symptoms, including arthritis, carditis, and neuropathy (2). In these instances, diagnosis is performed by serological testing to determine if the patient has been exposed to B. burgdorferi.The standard for serologic Lyme disease testing is a 2-tiered test recommended by the Centers for Disease Control and Prevention whereby the first tier is commonly an enzyme immunoassay ...

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Borrelia burgdorferi bba66 Gene Inactivation Results in Attenuated Mouse Infection by Tick Transmission

Cited by 32 publications

References 55 publications

Temperature-dependent sRNA transcriptome of the Lyme disease spirochete

Temperature-dependent sRNA transcriptome of the Lyme disease spirochete

Cyclic di-GMP Modulates Gene Expression in Lyme Disease Spirochetes at the Tick-Mammal Interface To Promote Spirochete Survival during the Blood Meal and Tick-to-Mammal Transmission

Evaluation of Selected Borrelia burgdorferi lp54 Plasmid-Encoded Gene Products Expressed during Mammalian Infection as Antigens To Improve Serodiagnostic Testing for Early Lyme Disease

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