Resurgence of persisting non-cultivable Borrelia burgdorferi following antibiotic treatment in mice

• Published in: PloS one Vol. 9; no. 1; p. e86907
• Main Authors: Hodzic, Emir, Imai, Denise, Feng, Sunlian, Barthold, Stephen W
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 23-01-2014; Public Library of Science (PLoS)
• Subjects: Analysis; Animal tissues; Animals; Anti-Bacterial Agents - pharmacology; Antibiotics; Arachnids; Arthritis; Biological effects; Biology; Borrelia burgdorferi; Borrelia burgdorferi - drug effects; Borrelia burgdorferi - physiology; Borreliosis; Ceftriaxone; Ceftriaxone - pharmacology; Cytokines; Deoxyribonucleic acid; DNA; DNA, Bacterial - genetics; Dogs; Enzyme-Linked Immunosorbent Assay; Female; Gene expression; Health aspects; Histopathology; Humans; Immunity; Immunoenzyme Techniques; Immunofluorescence; Immunohistochemistry; Infection; Infections; Laboratory animals; Lyme disease; Lyme Disease - drug therapy; Lyme Disease - genetics; Lyme Disease - microbiology; Medical research; Medicine; Mice; Mice, Inbred C3H; Pneumonia; Polymerase Chain Reaction; Primates; Recurrence; Ribonucleic acid; RNA; Rodents; Spirochaetales - drug effects; Spirochaetales - genetics; Spirochetes; Ticks; Tissues; Transcription; Transcription (Genetics); Veterinary medicine; Xenodiagnosis; United States > US; California
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0086907

The agent of Lyme borreliosis, Borrelia burgdorferi, evades host immunity and establishes persistent infections in its varied mammalian hosts. This persistent biology may pose challenges to effective antibiotic treatment. Experimental studies in dogs, mice, and non-human primates have found persistence of B. burgdorferi DNA following treatment with a variety of antibiotics, but persisting spirochetes are non-cultivable. Persistence of B. burgdorferi DNA has been documented in humans following treatment, but the significance remains unknown. The present study utilized a ceftriaxone treatment regimen in the C3H mouse model that resulted in persistence of non-cultivable B. burgdorferi in order to determine their long-term fate, and to examine their effects on the host. Results confirmed previous studies, in which B. burgdorferi could not be cultured from tissues, but low copy numbers of B. burgdorferi flaB DNA were detectable in tissues at 2, 4 and 8 months after completion of treatment, and the rate of PCR-positive tissues appeared to progressively decline over time. However, there was resurgence of spirochete flaB DNA in multiple tissues at 12 months, with flaB DNA copy levels nearly equivalent to those found in saline-treated mice. Despite the continued non-cultivable state, RNA transcription of multiple B. burgdorferi genes was detected in host tissues, flaB DNA was acquired by xenodiagnostic ticks, and spirochetal forms could be visualized within ticks and mouse tissues by immunofluorescence and immunohistochemistry, respectively. A number of host cytokines were up- or down-regulated in tissues of both saline- and antibiotic-treated mice in the absence of histopathology, indicating host response to the presence of non-cultivable, despite the lack of inflammation in tissues.