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Linda Bockenstedt, MD

Harold W. Jockers Professor of Medicine, Deputy Dean for Academic Affairs

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Linda Bockenstedt, MD

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Research Summary

My laboratory studies the pathogenesis of Lyme disease, a tick-borne infection with the spirochete Borrelia burgdorferi. We use the murine model of Lyme borreliosis to investigate the host immune response to the spirochete and mechanisms by which the spirochete persists in the host. Using molecular genomic, proteomic and imaging approaches, we are studying 1) spirochete interactions with ticks and host tissues in vivo in real-time; 2) mechanisms of spirochete evasion of innate and adaptive immune defenses, including biophysical studies of the spirochete; and 3) protein profiles of spirochetes during acute and chronic infection for improving diagnostic tests.

Specialized Terms: Pathogenesis of Lyme disease; Tick-borne infections; Innate immunity; Multiphoton imaging; Faculty development in context of team science

Extensive Research Description

Lyme borreliosis is an infectious disease caused by the
tick-transmitted spirochete Borrelia burgdorferi. Since its recognition in the United States in the early
1970’s, it has emerged as the most common vector-borne disease in North America
and a significant health care concern, with nearly 30,000 confirmed new cases
in 2009. The infection can present
with a localized skin rash at the site of tick bite or with involvement of
other organ systems, especially the heart, joints and nervous system. Although the infection is highly
responsive to antibiotic therapy when detected early, the time to symptom
resolution may be protracted. A
delay in diagnosis can result in disease manifestations, such as arthritis,
that persist despite antibiotics effective at earlier stages of the illness.

My laboratory used the murine model of Lyme borreliosis to
study the host immune response to B. burgdorferi in an effort to understand factors
that influence clearance of the organism and disease expression. Our published work has demonstrated the
importance of innate immunity, especially phagocytes and T cell independent antibody,
in control of pathogen burden and the role of IgG subtypes and Fc receptors in
severity of arthritis. Through
imaging modalities, we have begun to dissect the role of spirochete motility
and fluidity of its outer membrane in evasion of the innate and adaptive immune
responses. In collaboration with
Dr. Eric Dufresne (Yale Department of Engineering), we are using optical
tweezers and speckle microscopy to measure the mobility of proteins in the
spirochete outer membrane and the consequences of membrane fluidity on the
ability of phagocytes to capture and ingest B. burgdorferi. In vivo, we are using multiphoton
microscopy to measure in real time the speed and motility patterns of
spirochetes as they move between the tick and the mammal, and the requirement
for select B. burgdorferi proteins in this process. Using this system, we have also shown that the vast majority
of spirochetes are eliminated within the first few days of antibiotic therapy
for disseminated Lyme borreliosis, but antigenic debris can persist in tissue
adjacent to cartilaginous structures.
Our current studies are designed to investigate the duration of
persistence of this debris and the potential for it to incite inflammation,
which may contribute to persistent symptoms after treatment for Lyme disease.


In addition to pathogenesis studies, we are also working in
conjunction with L2 Diagnostics, Inc., to improve the diagnosis of Lyme
disease. We have identified panels
of B. burgdorferi antigens expressed at early and late stages of infection that
are underrepresented in lysates of cultured spirochetes, which are the
substrates of current serologic tests for Lyme disease. These antigens are being evaluated for use
as new antigens for diagnosing Lyme disease and for evaluating response to
therapy.

1. Real-time intravital microscopy of Borrelia burgdorferi infection in mice
This project is using multiphoton microscopy to define in real-time spirochete interactions between the feeding tick and the mammalian host, including modes of spirochete dissemination from the skin and evolving host immune responses.
2. Biophysical properties of Borrelia burgdorferi outer surface membrane
This collaborative project with Dr. Eric Dufresne (Yale Dept. of Engineering) employs optical tweezer technology and speckle microscopy to measure Borrelia burgdorferi outer membrane protein mobility and the relationship to directional forces exerted by spirochetes when trapped at one end.
3. Cutaneous host immune response to Borrelia burgdorferi.
This project seeks to understand the skin immune response to tick feeding and tick-introduced pathogens.
4. Development of improved diagnostic tests for Lyme disease
These projects, performed in collaboration with L2 Diagnostics, seek to develop improved diagnostic tests for Lyme disease based on in vivo expressed Borrelia burgdorferi proteins.
5. Innate immune pathways in elderly and immunosuppressed populations
This contract with Drs. Fikrig and Montgomery will analyze human
innate immune cell function in aging and medication-induced immunosuppression
and identify critical pathways and mechanisms that mediate impaired/dysregulated
immune responses in the elderly and immunosuppressed populations.

Coauthors

Research Interests

Faculty; Immunity, Innate; Lyme Disease; Rheumatology; Tick-Borne Diseases; Lyme Neuroborreliosis

Selected Publications

Clinical Trials

ConditionsStudy Title
ArthritisYale Rheumatology Program Patient Registry and Bio-Repository
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