Posted May 10, 2023

Laura Goodman, Ph.D., Cornell University
Luis Marcos, M.D., M.P.H., State University of New York, Stony Brook
Robert Lochhead, Ph.D., Medical College of Wisconsin
Neal Woodbury, Ph.D., Arizona State University

May is Lyme Disease Awareness Month, dedicated to improving public awareness and focusing efforts on reducing the burden of this prevalent disease spread through the bite of infected ticks. While most documented cases of Lyme disease in the United States are recorded in the Northeast, Mid-Atlantic, and North Central states, as well as northern California,¹ environmental changes are contributing to increased activity and range of the deer tick (Ixodes scapularis), leading to higher risk for contracting Lyme disease from this host.² Notably, from 1991 to 2018, the incidence and distribution of Lyme disease in the United States has doubled. Service Members are at significant risk for contracting Lyme disease in many field environments. Lyme disease has become a major public health concern because preventative measures are not always used, common clinical symptoms are mistaken for other illnesses, diagnostic tests may be lacking or inaccurate, and treatment protocols may not be administered or may be ineffective. Public awareness is critical to reducing the spread of Lyme disease and the financial costs associated with this illness.

While many associate Lyme disease with a characteristic “bull’s-eye” shaped erythema migrans (EM) rash on the body, it only signals early-stage infection and does not even appear in all cases. Other typical symptoms include fever, chills, fatigue, aching joints and muscles, swollen lymph nodes, and headaches. In the days to months after an infectious tick bite, Lyme disease symptoms can include more severe headaches and stiffness, inflammation and pain, arthritis, facial palsy, and heart palpitations or an irregular heartbeat (Lyme carditis).³ Current treatments for Lyme disease include antibiotics, which can effectively treat Lyme disease within several weeks after a tick bite. However, in rare cases, symptoms may persist after a lack of treatment or improper treatment for Lyme disease, known as post-treatment Lyme disease syndrome, or PTLDS. Many patients with PTLDS experience long-term fatigue and chronic symptoms, including Lyme arthritis, Lyme carditis, and/or neurological issues.⁴

The mission of the Congressionally Directed Medical Research Programs’ Tick-Borne Disease Research Program (TBDRP) is to understand the pathogenesis of Lyme disease and other tick-borne illnesses and conditions, and to deliver innovative solutions to prevent, diagnose, and treat their manifestations for the benefit of U.S. Service Members and the American public. When it comes to Lyme disease in particular, patient advocates have been calling for new, innovative diagnostic approaches for single or multiple tick-borne pathogens to better guide subsequent treatment and outcomes. For those patients already impacted by misdiagnosis or a lack of diagnosis, it is critical to understand the mechanisms underlying the potential long-term impacts of tick-borne illness on health. The brief summaries below describe several Lyme disease-focused awards from fiscal year 2021 (FY21) that are currently making strides toward accomplishing program goals.

With funding from an FY21 Idea Development Award, Dr. Laura Goodman’s team at Cornell University has partnered with Dr. Maria Diuk-Wasser at Columbia University to develop a rapid, point-of-care test capable of detecting all major tick-borne diseases and non-respiratory febrile illness pathogens known to affect humans, including those associated with Lyme disease. While traditional testing methods may include polymerase chain reaction (PCR) with primers (short sequences of DNA) to detect the presence of specific parts of pathogen genomes, they may not pick up on smaller fragments of DNA or unique genetic sequences that would differentiate pathogens even further by species or strain. For example, there are several species of the Lyme disease-causing bacteria, in the genus Borrelia. While Borrelia burgdorferi is found in the U.S., Borrelia afzelii and Borrelia garinii are the major pathogenic species in Europe.⁵ Dr. Goodman’s goal is to develop a comprehensive test utilizing Illumina sequencing to target a wide range of pathogens, including both RNA (arboviruses) and DNA (bacteria and parasites) detection. The benefits of using the Illumina method with hybrid capture next-generation sequencing are that it can utilize a larger number of probes (millions compared to hundreds used with PCR), it may detect novel pathogens that have yet to be sequenced, it reduces time and eliminates the need for larger lab equipment, and it can target and identify specific sequences of distinct pathogens in large, pooled samples. Dr. Goodman plans on developing the comprehensive test based on known pathogen targets, validating it in a laboratory setting and evaluating the capability of the assay to detect pathogens in ticks and surrogate animal samples from a field site with multiple tick species and pathogens present. They will also develop novel viral genes to test the ability of the assay to distinguish new, unknown pathogen strains. If successful, this comprehensive assay would greatly improve tick-borne infection diagnosis in the clinic and pathogen detection in the field, leading to better-guided treatment protocols and patient outcomes, as well as informed risk assessment, for Service Members and the American public.

Dr. Luis Marcos’ FY21 Idea Development Award has provided funding to support a longitudinal study to investigate co-infections of the Lyme disease-causing bacteria, Borrelia burgdorferi, and the parasite Babesia microti in patients. Both the bacteria and parasites can reside in infected deer ticks and may be transmitted to humans through tick bites. Dr. Marcos hypothesizes that coinfection may impact the severity of Lyme disease and contribute to greater bacterial burden, leading to the development of long-term symptoms and PTLDS. In collaboration with Dr. Dana Mordue from New York Medical College, the team will recruit patients with Lyme disease, patients with Lyme disease and babesia co-infection, and normal healthy controls. Patients will undergo blood draws, skin biopsies of EM rash (if present), clinical evaluation, and surveys at 0-, 1-, and 6-months post-treatment to compare symptoms and identify blood biomarkers. Blood samples from PTLDS patients (those with persistent symptoms 6 months post-treatment) will undergo RNA transcriptome testing that will be compared to results from subjects without PTLDS. A predictive modeling framework will be utilized on results from each study to identify differential blood biomarkers in hopes of better distinguishing and diagnosing patients with acute Lyme disease, babesia co-infections, and PTLDS. If successful, this project will help fill critical gaps in understanding the influence of tick-borne co-infections and improving diagnosis of tick-borne infection.

Dr. Robert Lochhead is utilizing funds from an FY21 Career Development Award to investigate Lyme disease infection-induced autoimmunity. Many Lyme disease patients experience long-term effects on health such as inflammation, arthritis, and autoimmunity, even years after receiving antibiotic treatment. Recent research detected the presence of peptidoglycan fragments, or cell-wall components of the Lyme disease-causing bacteria, Borrelia burgdorferi, in the joint fluid of Lyme arthritis patients. These results suggest that fragments of the infectious bacteria can remain inside the body long after initial infection. Dr. Lochhead’s lab has shown that peptidoglycan enhances immune responses that mediate inflammation and autoimmunity, particularly those from T cells and NK cells. This discovery has opened a new avenue to help understand how remaining peptidoglycan fragments can affect Lyme disease patient symptoms. This work will be presented at the upcoming American Association of Immunologists meeting in Washington, D.C., and is in preparation for publication. As an early career investigator, Dr. Lochhead hopes to advance his career in the field by assisting in the development of new animal models to better understand the relationship between Borrelia burgdorferi and persistent Lyme disease symptoms, such as chronic inflammation and autoimmunity.

Dr. Neal Woodbury has received funding from an FY21 Idea Development Award to investigate the use of immunogenic epitopes to detect antibodies associated with Lyme disease and other febrile illnesses. Epitopes are the parts of a pathogenic molecule (or antigen) that activate a host’s immune system to react to a foreign substance. Antigen epitopes can be present on various parts of any pathogenic molecule such as proteins, peptides, nucleic acids, etc., and will bind to a host’s antibodies (on B cells or T cells) to stimulate an immune response to stave off infection. Often, tick-borne diseases and febrile illnesses present with similar symptoms, such as fever, fatigue, and achy muscles. This can delay appropriate diagnostic measures such as the detection of antibodies that can indicate the presence of an invading tick-borne pathogen. Multiple co-infections in a host can also complicate clinical diagnosis and treatment of patients. Dr. Woodbury’s team is investigating antibody profiles in banked serum samples from patients with diagnostically confirmed tick-borne diseases such as Lyme disease, babesiosis, bartonellosis, ehrlichiosis, and other febrile illnesses such as influenza, West Nile Virus, and Parvovirus B19. Along with machine learning tactics to study the relationship between epitope sequence and antibody binding, results from Dr. Woodbury’s analysis of serum antibody profiles may allow better differentiation and diagnosis of Lyme disease and similar illnesses.

References:

¹Centers for Disease Control and Prevention. “Lyme Disease Frequently Asked Questions (FAQ)” https://www.cdc.gov/lyme/faq/index.html.

²United States Environmental Protection Agency. “Climate Change Indicators: Lyme Disease” https://www.epa.gov/climate-indicators/climate-change-indicators-lyme-disease#:~:text=Because%20tick%20activity%20depends%20on,be%20exposed%20to%20Lyme%20disease.

³Centers for Disease Control and Prevention. “Signs and Symptoms of Untreated Lyme Disease” https://www.cdc.gov/lyme/signs_symptoms/index.html.

⁴Centers for Disease Control and Prevention. “Post-Treatment Lyme Disease Syndrome” https://www.cdc.gov/lyme/postlds/index.html.

⁵European Centre for Disease Prevention and Control. “Factsheet About Borreliosis” https://www.ecdc.europa.eu/en/borreliosis/facts/factsheet.

Links:

Public and Technical Abstracts: Development of a Comprehensive Tick-Borne Pathogen and Febrile Illness Detection Panel

Public and Technical Abstracts: Host Peripheral Blood Biomarkers to Diagnose Active Lyme Disease and Post-Treatment Lyme Disease Syndrome

Public and Technical Abstracts: Borrelia burgdorferi Peptidoglycan Alters Host Immune Responses and Induces Autoimmunity

Public and Technical Abstracts: Identification of Immunogenic Epitopes for Lyme Disease Using Machine Learning-Based Comprehensive Reactivity Profiling of Patients' Antibodies

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