Measurement of Organ-Specific and Acute-Phase Blood Protein Levels in Early Lyme Disease

Summary

Reliable blood biomarkers for the early diagnosis of Lyme disease are needed. This study takes a focused approach to analyze serum proteins of Lyme disease patients relative to healthy controls to identify specific proteins that may serve as candidate blood biomarkers for a more reliable diagnostic test to detect Borrelia burgdorferi infection at the earliest stage possible.

Why was this study done?

The objective of this study was to identify blood proteins with altered concentrations in patients with early stage Lyme disease as compared to healthy controls. Such proteins are candidate biomarkers requiring further validation that may ultimately lead to the development of improved diagnostic tests for early Lyme disease, including patients with a negative antibody-based serologic test.

How was this study done?

This study used a targeted mass spectrometry-based method to measure specific blood proteins drawn from two key categories related to B. burgdorferi infection: (1) proteins involved in the host innate immune response during the acute phase of infection and (2) proteins specifically originating from single organs (organ-specific blood proteins) that are possible targets of the infection, for example, liver, brain, heart, and skin. Two independent Lyme disease cohorts, 40 patients total, were compared to 20 healthy controls.

What were the major findings?

In two independent early Lyme disease cohorts a set of blood proteins was identified that had significantly altered levels compared to healthy controls. These blood proteins were capable of distinguishing acute Lyme disease patients with high accuracy:

1. In the discovery cohort (obtained from the Johns Hopkins Lyme Disease Research Center’s SLICE Study) ten proteins were identified by t-test (ALDOB, AFM, APOA4, C9, CRP, CST6, FBP1, ITIH2, PGLYRP2, and S100A9). Ten proteins were also identified by (MVA) multivariable analysis (ALDOB, APOB, C9, CFHR, CRP, CST6, GC, F9, ITIH4, and PF4)
2. In a second independent Lyme disease cohort (from New York Medical College) (i) 6 proteins from the t-test set of 10 proteins and (ii) 9 of the 10 proteins in the MVA panel were identified with similar sensitivity and specificity as in the discovery cohort.
3. These Lyme disease-associated serum proteins (t-test set) and protein panel (MVA panel) identified acute Lyme disease in both seronegative and seropositive patients.

What is the impact of this work?

Early Lyme disease can be difficult to diagnose because early symptoms of Lyme disease mimic other illnesses such as flu, and the distinguishing erythema migrans rash is not always present or recognizable. In addition, available antibody-based blood tests are unreliable in early Lyme disease due to delays in initial antibody immune responses. Misdiagnosis and treatment delays can contribute to symptom severity and persistent illness.
This study identifies innate immune response and organ-specific blood proteins that may serve as candidate blood biomarkers for a more sensitive and reliable diagnostic test for early Lyme disease.
Further validation of these early Lyme disease associated blood proteins is needed.

This work was supported by

Bay Area Lyme Foundation, The Steven and Alexandra Cohen Foundation, NIH grant P30AR05350 (to J.N.A. and M.J.S.), P50GM076547 (L.H. and R.L.M.), the National Institute of Allergy and Infectious Diseases under Award NumberR21AI133335 (R.L.M.), and The Wilke Family Foundation. G.S.O. acknowledges NIH grants P30ES017885 and U24CA210967.

The authors thank the individuals with Lyme disease and healthy controls who participated in this study as well as ISB colleagues, Dr. Simon Evans who helpfully read and commented on the manuscript, and Dr. Max Robinson for helpful discussions on the statistics and analytical aspects of this study.

Publication Information

Measurement of Organ-Specific and Acute-Phase Blood Protein Levels in Early Lyme Disease Yong Zhou, Shizhen Qin, Mingjuan Sun, Li Tang, Xiaowei Yan, Taek-Kyun Kim, Juan Caballero, Gustavo Glusman, Mary E. Brunkow, Mark J. Soloski, Alison W. Rebman, Carol Scavarda, Denise Cooper, Gilbert S. Omenn, Robert L. Moritz, Gary P. Wormser, Nathan D. Price, John N. Aucott, and Leroy Hood
Journal of Proteome Research 2020 19 (1), 346-359
DOI: 10.1021/acs.jproteome.9b00569