Persistence of Borrelia burgdorferi in Rhesus Macaques following Antibiotic Treatment of Disseminated Infection

Monica E Embers,Lara Doyle,Jeanette E Purcell,Kathrine M Phillippi-Falkenstein,Nicole R Hasenkampf,Dale S Martin,Lisa Bowers,Marion S Ratterree,Stephen W Barthold,Juan T Borda,Mary B Jacobs,Sukanya Narasimhan,Emir Hodzic,Mario T Philipp,Jean Louis Herrmann

doi:10.1371/journal.pone.0029914

Monica E Embers, Lara Doyle + Show 13 more

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https://doi.org/10.1371/journal.pone.0029914

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Abstract

The persistence of symptoms in Lyme disease patients following antibiotic therapy, and their causes, continue to be a matter of intense controversy. The studies presented here explore antibiotic efficacy using nonhuman primates. Rhesus macaques were infected with B. burgdorferi and a portion received aggressive antibiotic therapy 4–6 months later. Multiple methods were utilized for detection of residual organisms, including the feeding of lab-reared ticks on monkeys (xenodiagnosis), culture, immunofluorescence and PCR. Antibody responses to the B. burgdorferi-specific C6 diagnostic peptide were measured longitudinally and declined in all treated animals. B. burgdorferi antigen, DNA and RNA were detected in the tissues of treated animals. Finally, small numbers of intact spirochetes were recovered by xenodiagnosis from treated monkeys. These results demonstrate that B. burgdorferi can withstand antibiotic treatment, administered post-dissemination, in a primate host. Though B. burgdorferi is not known to possess resistance mechanisms and is susceptible to the standard antibiotics (doxycycline, ceftriaxone) in vitro, it appears to become tolerant post-dissemination in the primate host. This finding raises important questions about the pathogenicity of antibiotic-tolerant persisters and whether or not they can contribute to symptoms post-treatment.

Highlights

Lyme borreliosis is caused by the spirochetes of the Borrelia burgdorferi sensu lato species complex
We performed two separate experiments to assess posttreatment persistence by B. burgdorferi in nonhuman primates with treatment administered at different phases of disseminated infection
The first (Experiment 1) was aimed at evaluating animals treated at the late disseminated phase of infection and the treatment regimen was chosen to correspond to the regimen used to treat human Post-treatment Lyme disease syndrome (PTLDS) patients in a clinical evaluation of treatment for this population [6]

Summary

Introduction

Lyme borreliosis is caused by the spirochetes of the Borrelia burgdorferi sensu lato species complex. The clinical progression of Lyme borreliosis may be divided into early-localized, earlydisseminated, and late stages. During the early-localized phase, the disease’s most prevalent sign is an erythematous skin rash known as erythema migrans. Patients may develop early-disseminated disease with dermatologic, rheumatologic, cardiac, and neurologic involvement. Patients with late disease present with arthritis or with neurologic manifestations [1]. The Infectious Diseases Society of America (IDSA) has issued guidelines for Lyme borreliosis therapy [2]. Signs and symptoms are usually successfully ameliorated with antimicrobial therapy. Some patients continue to have persistent subjective complaints [3,4] while a few patients fail to respond to antibiotic therapy, as made evident by signs of persistent infection [2,5]. The response to treatment in patients with late manifestations is typically slower [2] and sometimes remains incomplete

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