The Borrelia burgdorferi RelA/SpoT Homolog and Stringent Response Regulate Survival in the Tick Vector and Global Gene Expression during Starvation

Drecktrah, Dan; Lybecker, Meghan; Popitsch, Niko; Rescheneder, Philipp; Hall, Laura S.; Samuels, D. Scott

doi:10.1371/journal.ppat.1005160

Cited by 86 publications

(311 citation statements)

References 162 publications

(246 reference statements)

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“…The restoration of normal morphology upon the reintroduction of the gene in trans further reinforced the idea that the effect was specifically mediated by BbHtrA. Similar structurally heterogeneous entities have previously been recorded and are known to occur in spirochete populations that encounter stress, such as in unfed ticks or upon exposure to borreliacidal agents (46)(47)(48)(49). Here, we propose a critical role for BbHtrA, a high-temperature-induced protease, in the cellular regulation and stress tolerance of Lyme disease spirochetes.…”

Section: Discussionsupporting

confidence: 75%

HtrA, a Temperature- and Stationary Phase-Activated Protease Involved in Maturation of a Key Microbial Virulence Determinant, Facilitates Borrelia burgdorferi Infection in Mammalian Hosts

Sharma

Thakur

et al. 2016

Infect Immun

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d High-temperature requirement protease A (HtrA) represents a family of serine proteases that play important roles in microbial biology. Unlike the genomes of most organisms, that of Borrelia burgdorferi notably encodes a single HtrA gene product, termed BbHtrA. Previous studies identified a few substrates of BbHtrA; however, their physiological relevance could not be ascertained, as targeted deletion of the gene has not been successful. Here we show that BbhtrA transcripts are induced during spirochete growth either in the stationary phase or at elevated temperature. Successful generation of a BbhtrA deletion mutant and restoration by genetic complementation suggest a nonessential role for this protease in microbial viability; however, its remarkable growth, morphological, and structural defects during cultivation at 37°C confirm a high-temperature requirement for protease activation and function. The BbhtrA-deficient spirochetes were unable to establish infection of mice, as evidenced by assessment of culture, PCR, and serology. We show that transcript abundance as well as proteolytic processing of a borrelial protein required for cell fission and infectivity, BB0323, is impaired in BbhtrA mutants grown at 37°C, which likely contributed to their inability to survive in a mammalian host. Together, these results demonstrate the physiological relevance of a unique temperature-regulated borrelial protease, BbHtrA, which further enlightens our knowledge of intriguing aspects of spirochete biology and infectivity. L yme disease is a common vector-borne infectious disease in the Northern Hemisphere, posing a serious health threat to humans and animals (1-3). Newly revised estimates from the Centers for Disease Control and Prevention suggest that there are likely to be over 300,000 new cases per year in the United States alone, and a vaccine to prevent human infection is currently unavailable. The disease can be transmitted via the bite of the infected arthropod vector, the Ixodes scapularis tick, harboring the spirochete pathogen Borrelia burgdorferi, often resulting in serious illness in susceptible hosts (2, 3). While most Lyme disease cases can be treated with an antibiotic, a minority of patients will have persistent or relapsing nonobjective symptoms that vary in intensity, are nonresponsive to further antibiotic therapy, and are collectively termed chronic Lyme disease or posttreatment Lyme disease syndrome, the underlying mechanism and pathogenesis of which remain highly controversial (4). Detection of early Lyme disease, when antibiotic treatment is most effective, also remains challenging, as the infection reflects many nonspecific symptoms that are shared by many other febrile or influenza-like diseases (5, 6). Thus, the development of efficient diagnostics, vaccines, or new effective drugs is a high-priority goal that requires a thorough understanding of the unusual biology and infection process of this pathogen.The pathogen of Lyme disease exhibits evolutionary divergence from other bacteria, even related...

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Section: Discussionsupporting

confidence: 75%

HtrA, a Temperature- and Stationary Phase-Activated Protease Involved in Maturation of a Key Microbial Virulence Determinant, Facilitates Borrelia burgdorferi Infection in Mammalian Hosts

Sharma

Thakur

et al. 2016

Infect Immun

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“…In combination with density-dependent signals, these data reflect the role of RpoS in Spd-treated spirochetes. Both rpoZ and rel Bbu (bb0198) have been implicated in the metabolic response observed when spirochetes are shifted from minimal growth medium to nutritionally replete conditions that reflect the conditions in the midgut of tick before and after a blood meal (14,15). The transcript levels of rel Bbu were significantly elevated in B. burgdorferi grown to low density in the presence of Spd, while rel Bbu was downregulated in the Spd-treated samples grown to high density (Fig.…”

Section: Figmentioning

confidence: 95%

“…Rel Bbu is a bifunctional synthetase/hydrolase controlling the levels of guanosine tetra/pentaphosphate [(p)ppGpp]. (p)ppGpp has been shown to play a role in the regulation of the stringent response during the survival of B. burgdorferi in the tick vector or during starvation (14,15). While temperature, growth phase, or pH of the medium did not affect the transcriptional level of rel Bbu , shifting the spirochetes from nutritionally starved medium to that supplemented with rabbit serum significantly induced its transcription (15).…”

Section: Figmentioning

confidence: 99%

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Spermine and Spermidine Alter Gene Expression and Antigenic Profile of Borrelia burgdorferi

et al. 2017

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Borrelia burgdorferi, the agent of Lyme disease, responds to numerous host-derived signals to alter adaptive capabilities during its enzootic cycle in an arthropod vector and mammalian host. Molecular mechanisms that enable B. burgdorferi to detect, channel, and respond to these signals have become an intense area of study for developing strategies to limit transmission/infection. Bioinformatic analysis of the borrelial genome revealed the presence of polyamine transport components (PotA, PotB, PotC, and PotD), while homologs for polyamine biosynthesis were conspicuously absent. Although potABCD is cotranscribed, the level of PotA was elevated under in vitro growth conditions mimicking unfed ticks compared to the level in fed ticks, while the levels of PotD were similar under the aforementioned conditions in B. burgdorferi. Among several polyamines and polyamine precursors, supplementation of spermine or spermidine in the borrelial growth medium induced synthesis of major regulators of gene expression in B. burgdorferi, such as RpoS and BosR, with a concomitant increase in proteins that contribute to colonization and survival of B. burgdorferi in the mammalian host. Short transcripts of rpoS were elevated in response to spermidine, which was correlated with increased protein levels of RpoS. Transcriptional analysis of rpoZ and B. burgdorferi rel (rel Bbu ; bb0198) in the presence of spermidine revealed the interplay of multiple regulatory factors in B. burgdorferi gene expression. The effect of spermidine on the levels of select borrelial proteins was also influenced by serum factors. These studies suggest that multiple host-derived signals/nutrients and their transport systems contribute to B. burgdorferi adaptation during the vector and vertebrate host phases of infection.

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“…One such mechanism found in B. burgdorferi is the stringent response, which relies on the production of an alarmone, guanosine tetraphosphate (ppGpp), to ultimately increase protein recycling (13)(14)(15)(16)(17)(18). Another mechanism is the regulation of global protein translation levels by modulating ribosome activity.…”

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confidence: 99%

Long-Term Survival of Borrelia burgdorferi Lacking the Hibernation Promotion Factor Homolog in the Unfed Tick Vector

et al. 2015

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Borrelia burgdorferi, a causative agent of Lyme borreliosis, is a zoonotic pathogen that survives in nutrient-limited environments within a tick, prior to transmission to its mammalian host. Survival under these prolonged nutrient-limited conditions is thought to be similar to survival during stationary phase, which is characterized by growth cessation and decreased protein production. Multiple ribosome-associated proteins are implicated in stationary-phase survival of Escherichia coli. These proteins include hibernation-promoting factor (HPF), which dimerizes ribosomes and prevents translation of mRNA. Bioinformatic analyses indicate that B. burgdorferi harbors an hpf homolog, the bb0449 gene. BB0449 protein secondary structure modeling also predicted HPF-like structure and function. However, BB0449 protein was not localized in the ribosome-associated protein fraction of in vitro-grown B. burgdorferi. In wild-type B. burgdorferi, bb0449 transcript and BB0449 protein levels are low during various growth phases. These results are inconsistent with patterns of synthesis of HPF-like proteins in other bacterial species. In addition, two independently derived bb0449 mutants successfully completed the mouse-tick infectious cycle, indicating that bb0449 is not required for prolonged survival in the nutrient-limited environment in the unfed tick or any other stage of infection by B. burgdorferi. We suggest either that BB0449 is associated with ribosomes under specific conditions not yet identified or that BB0449 of B. burgdorferi has a function other than ribosome conformation modulation. L yme disease, the most common tick-transmitted disease in the United States (1), is caused by infection with the spirochete Borrelia burgdorferi (2, 3). This pathogen's complex infectious cycle includes an Ixodes tick vector and multiple vertebrate hosts. The Ixodes tick vector, like all hard ticks, has three developmental stages: larva, nymph, and adult. Typically, larval ticks become infected with B. burgdorferi by feeding on an infected vertebrate host, often a small mammal. B. burgdorferi survives within the tick midgut (2) as larval ticks molt into nymphs (transstadial passage) and the nymphs wait to feed again, which can include overwintering (4, 5). Following the larval molt, infected nymphs can transmit B. burgdorferi to naive vertebrate hosts, which, in turn, serve as a reservoir of spirochetes for larval ticks. After fed nymphs molt, infected adult ticks can also transmit B. burgdorferi, but adults typically feed on larger animals upon which larvae do not feed. Moreover, little or no transovarial transmission of spirochetes occurs (6, 7). Therefore, adult ticks do not significantly contribute to the maintenance of B. burgdorferi populations (8), and neither do humans, which are incidental hosts of B. burgdorferi. Hence, the larval and nymphal tick life stages are relevant to the zoonotic life cycle of B. burgdorferi.It has been generally accepted that B. burgdorferi populations are sustained in nature by the long-term infect...

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The Borrelia burgdorferi RelA/SpoT Homolog and Stringent Response Regulate Survival in the Tick Vector and Global Gene Expression during Starvation

Cited by 86 publications

References 162 publications

HtrA, a Temperature- and Stationary Phase-Activated Protease Involved in Maturation of a Key Microbial Virulence Determinant, Facilitates Borrelia burgdorferi Infection in Mammalian Hosts

HtrA, a Temperature- and Stationary Phase-Activated Protease Involved in Maturation of a Key Microbial Virulence Determinant, Facilitates Borrelia burgdorferi Infection in Mammalian Hosts

Spermine and Spermidine Alter Gene Expression and Antigenic Profile of Borrelia burgdorferi

Long-Term Survival of Borrelia burgdorferi Lacking the Hibernation Promotion Factor Homolog in the Unfed Tick Vector

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