Gene Regulation During the Enzootic Cycle of the Lyme Disease Spirochete

Samuels, D. Scott; Samuels, Leah R. N.

doi:10.1615/forumimmundisther.2017019469

Cited by 9 publications

(15 citation statements)

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“…Nucleotide second messengers have central roles in bacterial signaling systems (Pesavento and Hengge, 2009 ; Kalia et al, 2013 ; Fahmi et al, 2017 ; Nelson and Breaker, 2017 ; Hall and Lee, 2018 ), and B. burgdorferi is no exception (Novak et al, 2014 ; Caimano et al, 2016 ; Samuels and Samuels, 2016 ). Besides for (p)ppGpp and c-di-GMP, cyclic dimeric AMP (c-di-AMP) was recently recognized as an intracellular signal in B. burgdorferi (Ye et al, 2014 ; Savage et al, 2015 ).…”

Section: Resultsmentioning

confidence: 99%

“…B. burgdorferi must adapt to persist in the tick midgut during the molt into nymphs and then transmit back to a vertebrate during nymphal feeding (Radolf et al, 2012 ; Corona and Schwartz, 2015 ; Caimano et al, 2016 ). In order to survive these disparate environments, B. burgdorferi alters its pattern of gene expression in response to environmental signals, including temperature and nutrients (Radolf et al, 2012 ; Troxell and Yang, 2013 ; Iyer and Schwartz, 2016 ; Samuels and Samuels, 2016 ; Stevenson and Seshu, 2017 ). Central to this response is the RpoN-RpoS alternative sigma factor cascade that transcriptionally controls expression of numerous genes required for the transmission from the tick and the establishment of infection in the mammal (Hübner et al, 2001 ; Fisher et al, 2005 ; Burtnick et al, 2007 ; Caimano et al, 2007 ; Dunham-Ems et al, 2012 ; Ouyang et al, 2012 ; Grove et al, 2017 ).…”

Section: Introductionmentioning

confidence: 99%

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The Stringent Response-Regulated sRNA Transcriptome of Borrelia burgdorferi

Drecktrah

Hall

Rescheneder

et al. 2018

Front. Cell. Infect. Microbiol.

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The Lyme disease spirochete Borrelia (Borreliella) burgdorferi must tolerate nutrient stress to persist in the tick phase of its enzootic life cycle. We previously found that the stringent response mediated by RelBbu globally regulates gene expression to facilitate persistence in the tick vector. Here, we show that RelBbu regulates the expression of a swath of small RNAs (sRNA), affecting 36% of previously identified sRNAs in B. burgdorferi. This is the first sRNA regulatory mechanism identified in any spirochete. Threefold more sRNAs were RelBbu-upregulated than downregulated during nutrient stress and included antisense, intergenic and 5′ untranslated region sRNAs. RelBbu-regulated sRNAs associated with genes known to be important for host infection (bosR and dhhp) as well as persistence in the tick (glpF and hk1) were identified, suggesting potential mechanisms for post-transcriptional regulation of gene expression.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

The Stringent Response-Regulated sRNA Transcriptome of Borrelia burgdorferi

Drecktrah

Hall

Rescheneder

et al. 2018

Front. Cell. Infect. Microbiol.

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“…While there is a slight reduction in genomic equivalents of the ssrS null mutant observed in unfed nymphs that is restored in fed nymphs in the tick‐mouse model, this phenotype may have more severe consequences for B. burgdorferi in competition with other microbes in the complex environment of the tick midgut in nature. A number of studies have found global transcriptomic changes mediated by signaling pathways, in addition to those mediated by Rel Bbu (Drecktrah et al, ), to be important for persistence in the tick (Caimano et al, ; Samuels & Samuels, ), including the alternative sigma factor RpoS (Dunham‐Ems, Caimano, Eggers, & Radolf, ) and the Hk1/Rrp1 two‐component system regulating c‐di‐GMP levels (Caimano et al, ; He et al, ; Kostick et al, ; Sultan et al, ). In E. coli , 6S RNA causes an increase in relA transcription and, subsequently, (p)ppGpp levels (Cavanagh et al, ), so there may be positive feedback regulation.…”

Section: Discussionmentioning

confidence: 99%

“…The spirochete can be transmitted to and infect a new host as the nymph takes a blood meal, completing an enzootic cycle. B. burgdorferi adapts to and thrives in the different environments of the vector and host via the global regulation of gene expression (Iyer & Schwartz, ; Samuels & Samuels, ) mediated by the alternative sigma factor RpoS (σ S ) (Caimano et al, ; Fisher et al, ; Ouyang, Blevins, & Norgard, ), the stringent response via guanosine tetraphosphate and pentaphosphate [(p)ppGpp] (Bugrysheva et al, ; Drecktrah et al, ), and cyclic dimeric GMP (c‐di‐GMP) (Caimano et al, ; He et al, ; Rogers et al, ). While studies of these signaling systems have begun to uncover the gene products important for infectivity and persistence in the tick, our understanding of global transcriptional regulators remains incomplete.…”

Section: Introductionmentioning

confidence: 99%

Characterization of 6S RNA in the Lyme disease spirochete

Drecktrah

Hall

Brinkworth

et al. 2019

Molecular Microbiology

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6S RNA binds to RNA polymerase and regulates gene expression, contributing to bacterial adaptation to environmental stresses. In this study, we examined the role of 6S RNA in murine infectivity and tick persistence of the Lyme disease spirochete Borrelia (Borreliella) burgdorferi. B. burgdorferi 6S RNA (Bb6S RNA) binds to RNA polymerase, is expressed independent of growth phase or nutrient stress in culture, and is processed by RNase Y. We found that rny (bb0504), the gene encoding RNase Y, is essential for B. burgdorferi growth, while ssrS, the gene encoding 6S RNA, is not essential, indicating a broader role for RNase Y activity in the spirochete. Bb6S RNA regulates expression of the ospC and dbpA genes encoding outer surface protein C and decorin binding protein A, respectively, which are lipoproteins important for host infection. The highest levels of Bb6S RNA are found when the spirochete resides in unfed nymphs. ssrS mutants lacking Bb6S RNA were compromised for infectivity by needle inoculation, but injected mice seroconverted, indicating an ability to activate the adaptive immune response. ssrS mutants were successfully acquired by larval ticks and persisted through fed nymphs. Bb6S RNA is one of the first regulatory RNAs identified in B. burgdorferi that controls the expression of lipoproteins involved in host infectivity.

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“…The regulation of gene expression in B . burgdorferi is complex, often involving multiple layers of control [1,3,6].…”

Section: Introductionmentioning

confidence: 99%

Genome-wide screen identifies novel genes required for Borrelia burgdorferi survival in its Ixodes tick vector

et al. 2019

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Borrelia burgdorferi , the causative agent of Lyme disease in humans, is maintained in a complex biphasic life cycle, which alternates between tick and vertebrate hosts. To successfully survive and complete its enzootic cycle, B . burgdorferi adapts to diverse hosts by regulating genes required for survival in specific environments. Here we describe the first ever use of transposon insertion sequencing (Tn-seq) to identify genes required for B . burgdorferi survival in its tick host. We found that insertions into 46 genes resulted in a complete loss of recovery of mutants from larval Ixodes ticks. Insertions in an additional 56 genes resulted in a >90% decrease in fitness. The screen identified both previously known and new genes important for larval tick survival. Almost half of the genes required for survival in the tick encode proteins of unknown function, while a significant portion (over 20%) encode membrane-associated proteins or lipoproteins. We validated the results of the screen for five Tn mutants by performing individual competition assays using mutant and complemented strains. To better understand the role of one of these genes in tick survival, we conducted mechanistic studies of bb0017 , a gene previously shown to be required for resistance against oxidative stress. In this study we show that BB0017 affects the regulation of key borrelial virulence determinants. The application of Tn-seq to in vivo screening of B . burgdorferi in its natural vector is a powerful tool that can be used to address many different aspects of the host pathogen interaction.

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Gene Regulation During the Enzootic Cycle of the Lyme Disease Spirochete

Cited by 9 publications

References 97 publications

The Stringent Response-Regulated sRNA Transcriptome of Borrelia burgdorferi

The Stringent Response-Regulated sRNA Transcriptome of Borrelia burgdorferi

Characterization of 6S RNA in the Lyme disease spirochete

Genome-wide screen identifies novel genes required for Borrelia burgdorferi survival in its Ixodes tick vector

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