Sleeper cells: Stringent response & persistence in BB enzootic cycle

Topics with information and discussion about published studies related to Lyme disease and other tick-borne diseases.
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Sleeper cells: Stringent response & persistence in BB enzootic cycle

Post by RitaA » Sun 27 Aug 2017 5:56
Environ Microbiol. 2017 Aug 24. doi: 10.1111/1462-2920.13897. [Epub ahead of print]

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

Cabello FC1, Godfrey HP2, Bugrysheva J1,3, Newman SA4.

Author information

1 Departments of Microbiology and Immunology, New York Medical College, Valhalla, NY, USA.
2 Departments of Pathology, New York Medical College, Valhalla, NY, USA.
3 Centers for Disease Control and Prevention, Atlanta, GA, USA.
4 Departments of Cell Biology and Anatomy, New York Medical College, Valhalla, NY, USA.


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. This article is protected by copyright. All rights reserved.

© 2017 Society for Applied Microbiology and John Wiley & Sons Ltd.


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Re: Sleeper cells: Stringent response & persistence in BB enzootic cycle

Post by Lorima » Sun 27 Aug 2017 20:49

Interesting! This, from Valhalla (Wormser's institution) and the CDC? I haven't read it yet but will try to, soon.
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Re: Sleeper cells: Stringent response & persistence in BB enzootic cycle

Post by Psilociraptor » Sun 17 Dec 2017 0:21

Got around to reading this one finally. Overall pretty interesting, but confusing in sections. There are several statements the authors made that I would love clarified if anyone is capable. For example:

"Similarly, since null mutants of Rel and RpoS increase the frequency of round form morphotypes in vitro and in vivo (Dunham-Ems et al., 2012; Drecktrah et al., 2015), they might also act coordinately at specific stages to generate novel survival-related morphotypes during B. burgdorferi migration in nymphal ticks"

In another section the authors wrote that lack of (p)ppGpp lead to deficits in cell growth. Since these are supposed to be pathways that activate the stringent response why would deficiencies lead to features characteristic of the same stringent response they are supposed to be promoting? My expectation would have been excessive growth, motility, etc. At least until nutrient depletion led to aberrant synthesis. But I don't recall this ever being implied.

"This pattern of infection in the mammalian host suggests that following transmission of B. burgdorferi into the dermis by feeding nymphs, the stringent response is turned off because sufficient levels of nutrients are available in the dermis, blood and other host tissues (Corona and Schwartz, 2015). This could possibly account for the finding that mice were not infected following injection of a low concentration (1 × 104 cells) of a B. burgdorferi 297 rel mutant unable to synthetize (p)ppGpp"

How does the fact that the stringent response is turned off following transmission account for the lack of infectivity in mutants? If anything it seems to imply that there should be no effect on early infectivity since the stringent response is not heavily utilized in this phase. I don't seem to be following the authors logic

"Persisters also seem to be different from what have been termed dormant bacteria with a decreased rate of metabolism (Kim and Wood, 2017)"

Kim and Wood explicitly state in the last sentence of their paper (after arguing it the whole way through) that persister cells ARE dormant with a near absence of metabolism. So it's peculiar that they would cite Kim and Wood in a statement that seems to contradict the conclusion of their paper.

I feel like I'm missing something here. Most of the paper was pretty clear, but there were repeated statements like the ones above that make me feel I've missed some key component. Thanks in advance to anyone who can iron that out. Maybe i'll read it again in the morning and feel like a total dope, but for the moment I'm just not seeing through it.

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