A Longitudinal Systems-Level Analysis of the Human Immune Response During Lyme Disease

Lyme disease (LD) is the most common vector-borne disease in the United States, caused by the bacterium Borrelia burgdorferi. It is transmitted to humans through the bite of infected blacklegged ticks. The Centers for Disease Control and Prevention estimates that LD causes more than 300,000 illnesses every year in the United States and estimates the cost of testing alone at $492 million, although the total annual cost of LD to the US economy and its societal impact is likely much higher. However, despite this substantial public health burden, no approved vaccine exists and available diagnostic tests have severe limitations. Diagnostics which measure the antibody response to Borrelia infection remain negative for weeks after infection because antibodies can take several weeks to develop, while detection of Borrelia in the blood by culture or PCR-based diagnostics is unreliable due to the very low numbers of bacteria found in the blood of infected individuals.

Therefore, detailed studies of the human immune response to LD that may reveal early biomarkers of disease are warranted. Typical symptoms of LD include a characteristic skin rash called erythema migrans, fever, headache, and fatigue. If left untreated, infection can spread to joints, the heart, and the nervous system. Upon diagnosis, patients are usually treated with antibiotics, which are thought to destroy the bacterium. While most individuals resolve illness post antibiotic treatment, a subset of patients (approximately 10%-20%) continue to experience symptoms for 6 months or more after treatment, even though there is little evidence of persisting Borrelia infection in these individuals, a condition called Post Treatment Lyme Disease Syndrome (PTLDS). Currently, little is known about the underlying cause of PTLDS. We hypothesize that PTLDS may arise due to infection-induced changes in the immune system, which results in either tissue damage or autoimmunity. The goal of the proposed research is to characterize the acute immune response following infection (Aim 1), and identify if, and how, immune dysregulation contributes to the development of PTLDS (Aim 2).

To define the immune response to infection we will measure many immunological parameters including the concentrations of immunity-related proteins and immune cells in the blood of LD patients and healthy controls over time. These data will be integrated with clinical information to understand the mechanisms by which individuals respond to acute infection with Borrelia burgdorferi and the biological basis for transition from acute LD to PTLDS. This knowledge will be invaluable in developing better host-based diagnostic biomarkers of LD capable of accurately diagnosing individuals earlier than current tests, markers to assess disease prognosis, as well as in guiding vaccine efforts and future larger studies on PTLDS. It may also pave the way for developing new treatments that are milder than broad spectrum antibiotics like doxycycline. We expect that members of The United States Armed Forces will benefit from this work in many of the same ways as civilians; however, because many Service members operate heavily in areas endemic to LD and are at higher risk of contracting the disease, the results of this study will be especially valuable to them.