Bacterial and host factors in the pathogenesis of Lyme neuroborreliosis

莱姆神经疏螺旋体病发病机制中的细菌和宿主因素

• 批准号: 10443463
• 负责人: Catherine Ayn Brissette
• 金额: $ 42.3万
• 依托单位: UNIVERSITY OF NORTH DAKOTA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-06-23 至 2026-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10443463
• 关键词: Acute; Address; Affect; Animal Model; Anti-Inflammatory Agents; Antibiotic Therapy; Arthritis; Asia; Bacterial Adhesins; Biology; Blood Vessels; Borrelia; Borrelia burgdorferi; Brain; CD8-Positive T-Lymphocytes; Cardiac; Cells; Central Nervous System Diseases; Cephalic; Clinical; Clinical Research; Disease; Dura Mater; Encephalitis; Europe; Functional disorder; Genes; Genetic; Genotype; Headache; Heart; Hippocampus (Brain); Immune; Immune response; Immune signaling; Infection; Infiltration; Inflammation; Inflammatory; Integration Host Factors; Interferon Type II; Interferons; Intervention; Joints; Laboratories; Lead; Leukocytes; Lyme Arthritis; Lyme Disease; Lyme Neuroborreliosis; Lymphocyte; Macaca; Meningeal; Meninges; Meningitis; Modeling; Mus; Needles; Nervous system structure; Neuraxis; Neuritis; Neurologic; Neurologic Effect; Order Spirochaetales; Outcome; Pathogenesis; Pathology; Pathway interactions; Patients; Rattus; Reporting; Research; Research Support; Risk Factors; Role; Severities; Short-Term Memory; Signal Transduction; Sterility; Strategic Planning; Study models; T-Lymphocyte; Technology; Testing; Therapeutic Intervention; Tick-Borne Diseases; Time; Tissues; United States; United States National Institutes of Health; Vasculitis; Vector-transmitted infectious disease; Virulence Factors; Work; brain parenchyma; cytokine; density; diagnostic criteria; disabling symptom; experience; innovation; insight; lyme pathogenesis; lymphatic drainage; neuroinflammation; nonhuman primate; pathogen; pathogenic bacteria; response; targeted treatment; tick transmission; tick-borne pathogen; working group

The Lyme disease spirochete Borrelia burgdorferi causes an infection with diverse clinical outcomes, which can include arthritis as well as cardiac and neurological involvement. Lyme neuroborreliosis can range from headaches and mild meningitis to more serious manifestations including vasculitis. Despite antibiotic treatment, a proportion of patients continue to suffer from debilitating symptoms including neurological effects. The mechanisms of central nervous system (CNS) pathology as well as bacterial and host risk factors for these manifestations are poorly understood, largely due to the lack of a tractable laboratory model for the study of Lyme disease in the CNS. Previously, we reported the ability of Bb to colonize the dura mater of mice during late disseminated infection that was associated with an increase in T cells. We now show acute and persistent extravascular Bb colonization of the dura mater after both needle inoculation and tick transmission, accompanied by increases in expression of inflammatory cytokines; in addition, we observe a robust interferon (IFN) response in the dura mater comparable to that seen during murine Lyme arthritis. Dura colonization is associated with perivascular leukocyte infiltration and meningitis, demonstrating for the first time that Bb-infected mice can develop meningitis. We also demonstrate an increase in IFN-stimulated genes in both the cortex and hippocampus of infected mice, despite a lack of detectable spirochetes in the brain parenchyma. A sterile IFN response in the absence of Bb is unique to the brain parenchyma and could provide insights into the mechanism of inflammatory CNS pathology associated with this pathogen. An unanswered question is how specific bacterial virulence factors, in concert with the host response, intersect to cause CNS disease. Our tractable model will allow us to directly assess bacterial and host factors leading to more severe inflammatory CNS involvement, as well as test potential interventions. Our innovative proposal challenges existing paradigms, utilizes state-of-the-art technologies, and addresses critical barriers to Lyme neuroborreliosis research. Our central hypothesis is that specific bacterial factors engage the host immune response in a deleterious manner. We will address our central hypothesis with the following Specific Aims: Characterize the role of Borrelia genetics on CNS bacterial burden and host response. Working hypothesis: the severity of the CNS immune response during infection with Lyme disease Borrelia is dictated by the genetics of the infecting isolate. Delineate the role of immune signaling and other host responses in the CNS. Working hypothesis: IFN signaling affects the local inflammatory and cellular activation responses in the CNS. Modulate inflammation and pathology through targeted intervention. Working hypothesis: Decreasing inflammation at early time points, regardless of spirochete burden, will reduce meningitis and deleterious immune responses in the brain parenchyma. Our proposal directly addresses the NIH Strategic Plan for Tickborne Disease Research, including understanding both the fundamental biology of, and host interactions with, tickborne pathogens. Our proposal also addresses outstanding questions identified by the Pathogenesis and Pathophysiology of Lyme Disease Subcommittee of the HHS Tick Borne Disease Working Group, including what is the role of adhesins in dissemination to specific tissues. Our robust small animal model will allow us to fully characterize the CNS immune response to Bb infection, and to mechanistically define factors that contribute to neuroinflammation and disease. Identifying these factors will elucidate pathways to target for therapeutic intervention. Importantly, the results of our work will provide more sensitive and specific diagnostic criteria for Lyme neuroborreliosis and its sequalae.

莱姆病螺旋体伯氏疏螺旋体引起的感染具有多种临床结果，这可以