<snip>Longitudinal Transcriptome Analysis Reveals a Sustained Differential Gene Expression Signature in Patients Treated for Acute Lyme Disease
Jerome Bouqueta, Mark J. Soloskib, Andrea Sweic, Chris Cheadleb, Scot Federmana, Jean-Noel Billaudd, Alison W. Rebmanb, Beniwende Kabrea, Richard Halpertd, Meher Boorgulab, John N. Aucottb, Charles Y. Chiua
aDepartment of Laboratory Medicine, University of California, San Francisco, San Francisco, California, USA
bDepartment of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
cDepartment of Biology, San Francisco State University, San Francisco, California, USA
dQiagen Bioinformatics, Redwood City, California, USA
J.B., M.J.S., J.A., and C.Y.C. conceived the project and designed the research. J.B., M.J.S., A.S., and B.K. performed the experiments. J.A. and A.R. enrolled patients in the SLICE study and collected clinical and laboratory data. J.B., M.J.S., S.F., J.-N.B., R.H., M.B., C.C., and C.Y.C. analyzed next-generation sequencing and microarray data. J.B. and C.Y.C. wrote the manuscript.
Editor Alan G. Barbour, University of California Irvine
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.
IMPORTANCE Lyme disease is the most common tick-borne infection in the United States, and some patients report lingering symptoms lasting months to years despite antibiotic treatment. To better understand the role of the human host response in acute Lyme disease and the development of post-treatment symptoms, we conducted the first longitudinal gene expression (transcriptome) study of patients enrolled at the time of diagnosis and followed up for up to 6 months after treatment. Importantly, we found that the gene expression signature of early Lyme disease is distinct from that of other acute infectious diseases and persists for at least 3 weeks following infection. This study also uncovered multiple previously undescribed pathways and genes that may be useful in the future as human host biomarkers for diagnosis and that constitute potential targets for the development of new therapies.
<snip>The finding of a profound and sustained change in the transcriptome of acute Lyme disease patients refutes the idea that treatment and resolution of the infection result in a prompt return to a transcriptional baseline, as typically seen in the acute phase of other infections (16). In addition, failure to return to a transcriptome baseline cannot be accounted for solely by patients with persistent symptoms, given that no DEGs were found comparing Lyme disease patients with resolved illness to those with persistent symptoms (Table 2). Persistent transcriptional changes may be characteristic of not only Lyme disease but also a number of other infections. For example, viral clearance in hepatitis C patients did not result in normalization of the baseline transcriptome (17). To our knowledge, this is first time that sustained changes in the human host transcriptome have been reported for a bacterial infection after treatment with appropriate antibiotics. Persistence of such a signature for at least 3 weeks following infection suggests that a clinical diagnostic test for acute Lyme disease based on host gene expression is feasible. Such a test would also directly address the current diagnostic gap created by the “window period” between acute Lyme disease infection and the subsequent appearance of detectable antibody.
The news release:Importantly, Lyme disease patients did not show any changes in the calcium-dependent T-cell apoptosis pathway, in contrast to the marked down regulation observed in other bacterial and viral diseases (Fig. 4B). In addition, an absence of significant DEGs linked to B-cell development in Lyme disease relative to other infections was observed. These findings suggest that Lyme disease may be associated with a smaller proportion of B and T cells in peripheral blood than other diseases. Interestingly, suppression of long-lived humoral responses has been observed in a mouse model of Borrelia infection (31). The absence of DEGs corresponding to B-cell maturation may also potentially explain why prior infection with B. burgdorferi is associated with a serological response yet does not appear to confer immunity to reinfection. Certain alleles of HLA genes have been previously reported to be associated with serological responses to Lyme disease infection (32). Here we found that upregulation of certain HLA genes (HLA-DQA1, HLA-DQB1, HLA-DRB5) is associated with seronegativity in Lyme disease and may thus constitute potential diagnostic biomarkers for seronegative patients.
https://www.ucsf.edu/news/2016/02/40158 ... osing-lyme
University of California San Francisco ADVANCED
Gene Signature Could Lead To A New Way Of Diagnosing Lyme
By Laura Kurtzman on February 12, 2016