BB0744 Affects Tissue Tropism and Spatial Distribution of Borrelia burgdorferi

Wager, Beau; Shaw, Dana K.; Groshong, Ashley M.; Blevins, Jon S.; Skare, Jon T.

doi:10.1128/iai.00828-15

Cited by 14 publications

(28 citation statements)

References 68 publications

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“…3) (Barthold et al, 1991;2010a;Zeidner et al, 2001). In animal models of B. burgdorferi infection, there is a predilection of the spirochetes for collagenous tissues, which may be the result of borrelial adhesins for receptor molecules on the cells of these tissues (Coburn et al, 2013;Imai et al, 2013;Brissette and Gaultney, 2014;Caine and Coburn, 2015;Kumar et al, 2015;Wager et al, 2015;Zhi et al, 2015), propensity of the spirochete to invade native collagen matrices (Zambrano et al, 2004;Cabello et al, 2007), and/or the presence of antibodies preventing multiplication and invasion of other tissues and organs (Barthold et al, 1991;2010b;Bockenstedt et al, 2001).…”

Section: The Stringent Response and B Burgdorferi Residence In Vertementioning

confidence: 99%

Sleeper cells: the stringent response and persistence in the Borreliella (Borrelia) burgdorferi enzootic cycle

Cabello

Godfrey

Bugrysheva

et al. 2017

Environmental Microbiology

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Summary Infections with tick-transmitted Borreliella (Borrelia) burgdorferi, the cause of Lyme disease, represent an increasingly large public health problem in North America and Europe. The ability of these spirochetes to maintain themselves for extended periods of time in their tick vectors and vertebrate reservoirs is crucial for continuance of the enzootic cycle as well as for the increasing exposure of humans to them. The stringent response mediated by the alarmone (p)ppGpp has been determined to be a master regulator in B. burgdorferi. It modulates the expression of identified and unidentified open reading frames needed to deal with and overcome the many nutritional stresses and other challenges faced by the spirochete in ticks and animal reservoirs. The metabolic and morphologic changes resulting from activation of the stringent response in B. burgdorferi may also be involved in the recently described non-genetic phenotypic phenomenon of tolerance to otherwise lethal doses of antimicrobials and to other antimicrobial activities. It may thus constitute a linchpin in multiple aspects of infections with Lyme disease borrelia, providing a link between the micro-ecological challenges of its enzootic life-cycle and long-term residence in the tissues of its animal reservoirs, with the evolutionary side-effect of potential persistence in incidental human hosts.

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Section: The Stringent Response and B Burgdorferi Residence In Vertementioning

confidence: 99%

Sleeper cells: the stringent response and persistence in the Borreliella (Borrelia) burgdorferi enzootic cycle

Cabello

Godfrey

Bugrysheva

et al. 2017

Environmental Microbiology

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“…The bacterial loads in skin and heart tissues from mice infected with either the 5A18NP1 WT strain or different PEP-PTS mutants of B. burgdorferi were determined using quantitative PCR (qPCR) as described previously (33). Briefly, total DNA (bacterial and mammalian) was extracted from ϳ10 to 50 mg of skin and heart tissues using the DNeasy blood and tissue kit (Qiagen).…”

Section: Methodsmentioning

confidence: 99%

Phosphoenolpyruvate Phosphotransferase System Components Modulate Gene Transcription and Virulence of Borrelia burgdorferi

et al. 2016

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The phosphoenolpyruvate phosphotransferase system (PEP-PTS) and adenylate cyclase (AC) IV (encoded by BB0723 [cyaB]) are well conserved in different species of Borrelia. However, the functional roles of PEP-PTS and AC in the infectious cycle of Borrelia have not been characterized previously. We examined 12 PEP-PTS transporter component mutants by needle inoculation of mice to assess their ability to cause mouse infection. Transposon mutants with mutations in the EIIBC components (ptsG) (BB0645, thought to be involved in glucose-specific transport) were unable to cause infection in mice, while all other tested PEP-PTS mutants retained infectivity. Infectivity was partially restored in an in trans-complemented strain of the ptsG mutant. While the ptsG mutant survived normally in unfed as well as fed ticks, it was unable to cause infection in mice by tick transmission, suggesting that the function of ptsG is essential to establish infection by either needle inoculation or tick transmission. In Gramnegative organisms, the regulatory effects of the PEP-PTS are mediated by adenylate cyclase and cyclic AMP (cAMP) levels. A recombinant protein encoded by B. burgdorferi BB0723 (a putative cyaB homolog) was shown to have adenylate cyclase activity in vitro; however, mutants with mutations in this gene were fully infectious in the tick-mouse infection cycle, indicating that its function is not required in this process. By transcriptome analysis, we demonstrated that the ptsG gene may directly or indirectly modulate gene expression of Borrelia burgdorferi. Overall, the PEP-PTS glucose transporter PtsG appears to play important roles in the pathogenesis of B. burgdorferi that extend beyond its transport functions.

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“…However, when a region of lp25, containing the bbe22 gene, is provided in trans infectivity is restored and provides selective pressure for the maintenance of plasmids encoding it during experimental infection [60, 61]. The shuttle vector pBBE22 luc used here contains bbe22 and the firefly luciferase reporter that facilitates bioluminescent imaging as reported previously [60,62,63].…”

Section: Resultsmentioning

confidence: 99%

“…The ittA complement strain was designated DM113. Following the aforementioned screen of the ittA ::Str R mutant strain DM103 and the complement strain DM113, both were transformed with pBBE22 luc so they could be tested in the murine experimental model of infection using a firefly luciferase reporter [60,62,63]. Note that all strains maintained plasmid content identical to the parent strain (data not shown).…”

Section: Resultsmentioning

confidence: 99%

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The Intergenic Small Non-Coding RNA ittA is Required for Optimal Infectivity and Tissue Tropism in Borrelia burgdorferi

Medina-Pérez

Wager

Troy

et al. 2020

Preprint

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ABSTRACTPost-transcriptional regulation via small regulatory RNAs (sRNAs) has been implicated in diverse regulatory processes in bacteria, including virulence. One class of sRNAs, termed trans-acting sRNAs, can affect the stability and/or the translational efficiency of regulated transcripts. In this study, we utilized a collaborative approach that employed data from infection with the Borrelia burgdorferi Tn library, coupled with Tn-seq, together with borrelial sRNA and total RNA transcriptomes, to identify an intergenic trans-acting sRNA, which we designate here as ittA for infectivity-associated and tissue-tropic sRNA locus A. The genetic inactivation of ittA resulted in a significant attenuation in infectivity, with decreased spirochetal load in ear, heart, skin and joint tissues. In addition, the ittA mutant did not disseminate to peripheral skin sites or heart tissue, suggesting a role for ittA in regulating a tissue-tropic response. RNA-Seq analysis determined that 19 transcripts were differentially expressed in the ittA mutant relative to its genetic parent, including vraA, bba66, ospD and oms28 (bba74). Subsequent proteomic analyses also showed a significant decrease of OspD and Oms28 (BBA74) proteins. To our knowledge this is the first documented intergenic sRNA that alters the infectivity potential of B. burgdorferi.AUTHOR SUMMARYLyme disease is a tick-borne infection mediated by the spirochetal bacterium, Borrelia burgdorferi, that is responsible for greater than 300,000 infections in the United States per year. As such, additional knowledge regarding how this pathogen modulates its regulatory armamentarium is needed to understand how B. burgdorferi establishes and maintains infection. The identification and characterization of small, non-coding RNA molecules in living systems, designated as sRNAs, has recalibrated how we view post-transcriptional regulation. Recently, over 1,000 sRNAs were identified in B. burgdorferi. Despite the identification of these sRNAs, we do not understand how they affect infectivity or B. burgdorferi pathogenesis related outcomes. Here, we characterize the ittA B. burgdorferi sRNA and show that it is essential for optimal infection using murine experimental infection as our readout. We also track the effect of this sRNA on the transcriptional and proteomic profile as the first step in providing mechanistic insight into how this important sRNA mediates its regulatory effect.

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BB0744 Affects Tissue Tropism and Spatial Distribution of Borrelia burgdorferi

Cited by 14 publications

References 68 publications

Sleeper cells: the stringent response and persistence in the Borreliella (Borrelia) burgdorferi enzootic cycle

Sleeper cells: the stringent response and persistence in the Borreliella (Borrelia) burgdorferi enzootic cycle

Phosphoenolpyruvate Phosphotransferase System Components Modulate Gene Transcription and Virulence of Borrelia burgdorferi

The Intergenic Small Non-Coding RNA ittA is Required for Optimal Infectivity and Tissue Tropism in Borrelia burgdorferi

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