(provided by the applicant): Lyme disease is the most frequently reported tick-borne infectious disease in the United States and both its incidence and range are increasing. Early diagnosis and treatment of Lyme disease is critical to prevent disease progression and sequellae. Current laboratory diagnostics are primarily serologic assays and they fail in a number of key areas. They are insufficiently specific, not sensitive in early Lyme disease and cannot determine treatment response. More importantly, because serological assays are based on the presence of antibodies, they are incapable of discriminating between active infection and immunological memory due to prior, resolved infection with Borrelia burgdorferi. New paradigms and assays are needed to address these gaps in our diagnostic capabilities. Here we propose a new approach. We will utilize differential gene expression analysis to identify a signature response to B. burgdorferi in the blood of Lyme disease patients, with the long-term objective of developing a reliable gene-based diagnostic test for active infection. Specifically we propose to: 1) use microarray analysis to identify genes differentially expressed in peripheral blood mononuclear cells (PBMCs) isolated from patients with active, culture-confirmed Lyme disease and compare the results to PBMCs from healthy donors;2) identify a set of discriminator genes predictive of B. burgdorferi infection, as opposed to infection by other common blood-borne bacterial pathogens, using a supervised learning approach of predictor selection;3) assess expression levels of genes identified as B. burgdorferi-specific indicator genes by real-time RT-PCR in paired acute and convalescent patient samples obtained following standard antibiotic treatment in patients with resolution of symptoms. This will provide information on the gene expression over time in successfully-treated patients and should define a subset of discriminator genes characteristic of active, as opposed to resolved, B. burgdorferi infection. These studies are expected to result in the identification of a defined set of indicator genes which are significantly and uniquely regulated in patients with active Lyme disease as opposed to patients that have been successfully treated with antibiotics or individuals with other common blood-borne bacterial infections. Once identified, this subset of classifier genes can serve as the basis for development of a sensitive and specific diagnostic test for active B. burgdorferi infection.

Public Health Relevance

Lyme disease, the most frequently reported tick-borne disease in the United States, is caused by infection with the spirochete Borrelia burgdorferi and diagnosis is currently based on serological tests which lack sensitivity and specificity, especially in early disease, and do not discriminate between active infection and prior, resolved infection with B. burgdorferi. The proposed studies are expected to result in the identification of a defined set of indicator genes which are significantly and uniquely regulated in patients with active Lyme disease as opposed to patients with other common blood-borne bacterial infections or individuals with antibiotic-treated, resolved Lyme disease with or without ongoing symptoms. Once identified, this subset of classifier genes could be employed as the basis for development of a sensitive and specific gene-based diagnostic test for active B. burgdorferi infection.

Agency
National Institute of Health (NIH)
Institute
Centers for Disease Control and Prevention (CDC)
Type
Research Project--Cooperative Agreements (U01)
Project #
5U01CK000153-03
Application #
8324940
Study Section
Special Emphasis Panel (ZCD1-CJM (13))
Project Start
2010-09-01
Project End
2013-08-31
Budget Start
2012-09-01
Budget End
2013-08-31
Support Year
3
Fiscal Year
2012
Total Cost
$249,945
Indirect Cost
$92,747
Name
New York Medical College
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
041907486
City
Valhalla
State
NY
Country
United States
Zip Code
10595