Monday, April 29, 2024
4/29/2024
ABSTRACT As an organism that persists in its natural hosts for long periods of time, Borrelia burgdorferi, the causative agent of Lyme disease, has adapted many strategies for survival and evasion of host immune responses. It has a very small genome and is unable to produce many essential nutrients for itself and is instead, dependent upon utilizing them from its environment. We have recently shown that B. burgdorferi is able to acquire host phospholipids and deploy them, intact, in its membrane. A cost of utilizing host phospholipids is that it may result in production, or de-repression of autoantibodies to host phospholipid targets. Indeed, in our preliminary studies, we found that mice and humans infected with B. burgdorferi produce antibodies to host phospholipids that the organism itself does not produce. Antibodies to phospholipids arise quicker than other antibodies to B. burgdorferi and also appear to resolve more quickly, as might be expected since autoantibody production is typically tightly regulated. However, in patients with PTLDS as compared with patients who resolve their symptoms after treatment for Lyme, there appears to be increased levels of anti-phospholipid antibodies. It is unknown whether these antibodies may be pathogenic or are just a marker for PTLDS. In this proposal, we will explore the development of anti-lipid/phospholipid antibodies during Lyme disease and their potential role in PTLDS. In Aim 1, we will determine the extent of anti-lipid/phospholipid development at different stages of disease and determine their relationship to disease resolution/persistent symptoms in patients with Lyme disease. In Aim 2, we will examine binding of these antibodies to human cells and tissues and look for the presence of immune complexes which are often deposited in auto-immune diseases. Finally, in Aim 3, we will explore a new animal model for PTLDS. A recent study has shown that injection of antibodies from patients with fibromyalgia, a disease with marked similarities to PTLDS in symptoms, into mice results in hypersensitivity to pain and cold as well as changes in locomotion. Histological studies have shown binding of the human antibodies to neural tissues and macrophages. We will test a similar model using serum from patients with PTLDS, recovered Lyme disease and fibromyalgia. In our preliminary studies, we have found increased binding of antibodies from PTLDS patients to mouse brain tissue compared with binding from healthy control antibodies. The discovery of autoantibodies to lipids/phospholipids opens a new area for discovery in the pathogenesis for Lyme disease and may lead to better diagnostic tests and a new understanding of the pathogenesis of this disease.
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