Longitudinal Transcriptome Analysis Reveals a Sustained Differential Gene Expression Signature in Patients Treated for Acute Lyme Disease.

Jerome Bouquet,Jean-Noel Billaud,Mark J Soloski,Charles Y Chiu,John N Aucott,Chris Cheadle,Andrea Swei,Alison W Rebman,Meher Boorgula,Richard Halpert,Scot Federman,Beniwende Kabre

doi:10.1128/mbio.00100-16

Abstract

ABSTRACTLyme disease is a tick-borne illness caused by the bacterium Borrelia burgdorferi, and approximately 10 to 20% of patients report persistent symptoms lasting months to years despite appropriate treatment with antibiotics. To gain insights into the molecular basis of acute Lyme disease and the ensuing development of post-treatment symptoms, we conducted a longitudinal transcriptome study of 29 Lyme disease patients (and 13 matched controls) enrolled at the time of diagnosis and followed for up to 6 months. The differential gene expression signature of Lyme disease following the acute phase of infection persisted for at least 3 weeks and had fewer than 44% differentially expressed genes (DEGs) in common with other infectious or noninfectious syndromes. Early Lyme disease prior to antibiotic therapy was characterized by marked upregulation of Toll-like receptor signaling but lack of activation of the inflammatory T-cell apoptotic and B-cell developmental pathways seen in other acute infectious syndromes. Six months after completion of therapy, Lyme disease patients were found to have 31 to 60% of their pathways in common with three different immune-mediated chronic diseases. No differential gene expression signature was observed between Lyme disease patients with resolved illness to those with persistent symptoms at 6 months post-treatment. The identification of a sustained differential gene expression signature in Lyme disease suggests that a panel of selected human host-based biomarkers may address the need for sensitive clinical diagnostics during the “window period” of infection prior to the appearance of a detectable antibody response and may also inform the development of new therapeutic targets.

Highlights

Lyme disease, a systemic tick-borne infection caused by the bacterial spirochete Borrelia burgdorferi, is the most common vector-borne disease in the United States and Europe [1]
Transcriptome profiling by RNA sequencing (RNA-Seq) and pathway analysis were performed with peripheral blood mononuclear cells (PBMCs) samples collected at three time points, V1, V2, and V5 (6 months after the completion of therapy) (Fig. 1)
The 29 Lyme disease patients were enrolled in a single season at the same geographic location, an outpatient clinic in suburban Maryland

Summary

Introduction

A systemic tick-borne infection caused by the bacterial spirochete Borrelia burgdorferi, is the most common vector-borne disease in the United States and Europe [1]. The proportion of Lyme disease patients with persistent symptoms varies greatly, from 0 to 50%, depending on the cohort of interest and the case definition used [4, 5]. When lingering or recurrent symptoms are associated with a functional decline and persist for greater than 6 months, patients are considered to meet clinical criteria for post-treatment Lyme disease syndrome (PTLDS) [6], the exact molecular mechanisms underlying this condition remain unknown. We applied next-generation sequencing of peripheral blood mononuclear cells (PBMCs) to investigate the transcriptomes of 29 patients with acute Lyme disease longitudinally from the time of diagnosis to 6 months post-treatment and those of 13 matched controls. We performed network and pathway analyses in order to gain insights into the molecular mechanisms underpinning acute Lyme disease and post-treatment symptoms and to discover potential diagnostic biomarkers

Methods

Results

Conclusion