The Functional and Molecular Effects of Doxycycline Treatment on Borrelia burgdorferi Phenotype

Abstract

Recent studies have shown that Borrelia burgdorferi can form antibiotic-tolerant persisters in the presence of microbiostatic drugs such as doxycycline. Precisely how this occurs is yet unknown. Our goal was to examine gene transcription by B. burgdorferi following doxycycline treatment in an effort to identify both persister-associated genes and possible targets for antimicrobial intervention. To do so, we performed next-generation RNA sequencing on doxycycline-treated spirochetes and treated spirochetes following regrowth, comparing them to untreated B. burgdorferi . A number of genes were perturbed and most of those which were statistically significant were down-regulated in the treated versus the untreated or treated/re-grown. Genes upregulated in the treated B. burgdorferi included a number of Erp genes and rplU , a 50S ribosomal protein. Among those genes associated with post-treatment regrowth were bba74 (Oms28), bba03 , several peptide ABC transporters, ospA, ospB , ospC , dbpA and bba62 . Studies are underway to determine if these same genes are perturbed in B. burgdorferi treated with doxycycline in a host environment.

Lyme Disease Frontiers: Reconciling Borrelia Biology and Clinical Conundrums

“…Although the extended viability, recovery, and regrowth of these remaining cells were not assessed, the distinct gene expression profiles suggest that drug exposure may be a primary trigger of a physiological response, rather than simply enriching for stochastically pre-formed persisters. A subsequent study profiled the transcriptome of cells under doxycycline MBC and during drug-free rebound, and found a pattern speculated to represent onset and resolution of dormancy [267]. Moreover, treated cells were found to retain some infectious capacity in an immunocompetent murine host [267].…”

“…A subsequent study profiled the transcriptome of cells under doxycycline MBC and during drug-free rebound, and found a pattern speculated to represent onset and resolution of dormancy [267]. Moreover, treated cells were found to retain some infectious capacity in an immunocompetent murine host [267].…”

“…This speculation is likewise spurred by in vitro work, discussed in Section 5.1.3, that suggests that Bb strains can differ in their MICs, and that antibiotics may instigate persistent bacterial phenotypes. Ideally a font-line therapeutic agent should not push surviving cells toward a treatment-intractable state, and as described above, some research is now focusing on the relevance of the transcriptomic changes that occur in Borrelia in response to conventional antibiotic treatment [267].…”

Recent Progress in Lyme Disease and Remaining Challenges

“…B. burgdorferi may enter dormancy during long periods of nutrient deprivation within the tick or following treatment of a mammalian host with a bacteriostatic antibiotic such as doxycycline. The stress response of the bacteria to nutrient deprivation has been described (257) and this capability to survive harsh environments may well contribute to antibiotic tolerance as well (258).…”

Report of the Pathogenesis and Pathophysiology of Lyme Disease Subcommittee of the HHS Tick Borne Disease Working Group

“…Evidence now exists, from the results of experiments in both murine and non-human primate models, that persisting B. burgdorferi can be metabolically active, expressing certain bacterial genes and inducing gene expression changes in the infected host, despite being non-culturable following antibiotic treatment (22,(37)(38)(39). In one model, the spirochetes localized to the dura mater of the brain, associated with large-scale changes in gene expression of pro-inflammatory cytokines and chemokines (40,41).…”