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

Abstract

Lyme 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.

Functional and Genomic Architecture of Borrelia burgdorferi -Induced Cytokine Responses in Humans

“…To determine whether HIF-1a-mediated glucose metabolism is also involved in patients, we analyzed PBMC transcriptomic profiles of 29 patients with physician-documented EM from a previously published study (Bouquet et al, 2016). These data corroborated our in vitro findings, with HIF1A mRNA being significantly upregulated in PBMCs at the time of diagnosis (T = 0) and 2 weeks thereafter (T = 2w).…”

Global Transcriptome Analysis Identifies a Diagnostic Signature for Early Disseminated Lyme Disease and Its Resolution

“…In addition, the 20-gene classifier set clearly distinguishes B. burgdorferi infection from that caused by influenza A, although both pathogens potently stimulate the interferon signaling pathway (33). Bouquet and colleagues also examined the transcriptional profile in PBMCs of LD patients with EM before antibiotic treatment, 3 weeks later, and then 6 months after the completion of antibiotic therapy (34). There is general consensus between Bouquet et al and a major finding of the present study: acute infection with B. burgdorferi elicits a distinct gene expression profile in patient blood that persists for at least 3 weeks after infection.…”

Clinical metagenomics

“…Interrogation of RNA reads from microorganisms corresponding to active microbial gene expression might enable the dis crimination between infection versus colonization 25 and live (viable) versus dead organisms 79 . Moreover, RNA seq analyses of the human host can be used to identify novel or underappreciated host-microbial interactions directly from clinical samples, as previously shown for patients with Lyme disease 68 , dengue 80 or malaria 81 . RNA seq may be particularly useful in clinical cases in which the causative pathogen is only transiently present (such as early Lyme disease 82 or arboviral infections, including West Nile virus 83 or ZIKV 84 ); analogous to serologic testing, indirect diagnosis of infections may be possible on the basis of a pathogen specific human host response.…”