Posted May 11, 2021

Dr. Archana Dhasarathy, Ph.D., University of North Dakota School of Medicine
Dr. Cherie Marvel, Ph.D., Johns Hopkins University
Dr. Maria Elena Bottazzi, Ph.D., Texas Children's Hospital Center for Vaccine Development and Baylor College of Medicine

May is Lyme Disease Awareness Month, which aims to increase public knowledge of Lyme disease and to bring affected patients, their physicians and caregivers together with others to form strong supportive communities. Lyme disease, most frequently caused by the spirochete bacterium Borrelia burgdorferi (Bb), is the most commonly diagnosed tick-borne infection, with the number of confirmed and suspected cases in the U.S. generally increasing each year. Similar increases in cases have been reported for military Service Members and their beneficiaries. Symptoms of early Lyme disease can be similar to those experienced with other acute illnesses such as influenza and, for many patients resolve with a course of antibiotics. Other patients, however, can progress several weeks or months after tick bite to chronic disease that may include neurological complications, cardiac dysfunction, and immune conditions including Lyme arthritis, and for some, these symptoms are persistent. There are also a substantial portion of Lyme disease patients that remain undiagnosed or misdiagnosed, typically because they do not recall being bitten by a tick or because their clinical parameters and serology-based two-tiered testing results do not meet the thresholds required for formal diagnosis. Thus, the true burden and impact of Lyme disease remains largely unknown.

Through the CDMRP two-tier review process, each year TBDRP peer and programmatic reviewers evaluate research proposals and make funding recommendations based on scientific merit and programmatic priorities. The TBDRP further distinguishes itself from other funding agencies by emphasizing the impact of the research on addressing the burden of tick-borne diseases on military Service Members and their beneficiaries. In support of the awards recommended for funding since the inception of the TBDRP in fiscal year (FY) 2016, approximately half of the program’s total research budget has funded Lyme disease research focused on prevention and reducing public and military health burden, improving treatment options and diagnostic assays, and understanding pathogenic mechanisms. Brief summaries of three FY19 TBDRP awards focused on addressing important needs in the field of Lyme disease are described below.

Dr. Archana Dhasarathy at the University of North Dakota School of Medicine is working with co-investigator Dr. Catherine Brissette to study underlying mechanisms of persistent Lyme disease, specifically Lyme arthritis, by evaluating the epigenetic changes that occur post infection with Bb. Using human synoviocytes (cells found in the joints) and murine models of arthritis, Dr. Dhasarathy, Dr. Brissette, and their team aim to identify transcriptomic changes, characterize inflammatory markers indicative of arthritis and track epigenetic changes in chromatin causing cells to be poised for rapid and robust inflammatory responses to pro-inflammatory signals. Dr. Dhasarathy hypothesizes that infection with Bb creates epigenetic marks that persist years after the infection is treated, similar to a bookmark, to “remember” that these inflammatory genes were once turned on. By studying and describing these markers, the team hopes to provide insight into the molecular pathogenesis of Lyme arthritis, in turn allowing physicians to better manage and treat the Lyme disease as well as to monitor disease progression and resolution.

Dr. Cherie Marvel at Johns Hopkins University aims to yield insight into the pathogenesis of post-treatment Lyme disease syndrome (PTLDS) in which patients treated for Lyme disease continue to suffer chronic symptoms that can include neurocognitive impairment, fatigue, musculoskeletal pain and neurological symptoms. Unfortunately, there is currently no diagnostic or prognostic to determine if a patient has, or will, develop chronic neurocognitive dysfunctions as a result of PTLDS. Dr. Marvel and her team hypothesize that patients with PTLDS that present with neurological and/or neurocognitive symptoms will display changes in the brain (structural, functional, and/or molecular) as a result of the immune response to infection. Using functional Magnetic Resonance Imaging (fMRI) and Diffusion Tensor Imaging (DTI), the team will assess brain activity and structural integrity. Patients will also undergo physical exams, cognitive evaluations and surveys and questionnaires regarding their general and neurological symptoms. Patients will also provide serum and cerebrospinal fluid samples to allow for the evaluation of inflammatory cytokines, autoantibodies and antigens which will all be correlated to findings of patients’ neurocognitive and imaging results. The completion of these studies will improve patient care by providing clinicians with markers to be able to determine who has or may be at risk for developing persistent neurologic signs and symptoms as a result of Lyme disease, which may provide the field with new therapeutic targets.

Dr. Maria Elena Bottazzi at Texas Children’s Hospital Center for Vaccine Development and Baylor College of Medicine together with scientists at the Wadsworth Center, New York Department of Health, aims to fill a gap in Lyme disease prevention by developing a vaccine made from a mutant outer membrane protein of Borrelia burgdorferi sensu lato (Bbsl), called CspZ-YA. Normally, CspZ binds to a key regulator of the Complement cascade, a pathway involved in bacterial killing. The binding of CspZ to this key regulator inhibits this bacterial killing, thus providing a survival advantage to the pathogen. The mutant CspZ-YA cannot bind to the Complement regulator, and thus this immunogenic mutant outer membrane protein, which is expressed only in mammalian hosts, may serve as a putative vaccine candidate. CspZ-YA has resulted in the successful generation of a robust antibody response and protective efficacy in animal studies; however, the production of this vaccine is not scalable. In the current TBDRP-funded studies, Dr. Bottazzi and her team will develop processes to manufacture CspZ-YA and evaluate different vaccine regimens and immune correlates of protection in vivo. The successful completion of these studies will establish a vaccine candidate for Lyme disease, elucidate immune correlates of protection and provide a cost effective, scalable production pipeline for Bbsl antigenic vaccines.

Links:

Public and Technical Abstracts: Epigenetic and Transcriptional Memory Mechanisms in Lyme Arthritis

Public and Technical Abstracts: Identifying the Underlying Mechanisms of Persistent Neurologic Symptoms Associated with Posttreatment Lyme Disease Syndrome

Public and Technical Abstracts: Development of a Recombinant CspZ Vaccine Against Lyme Disease Infection

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