B. burgdorferi interactions with the blood-CSF barrier: Development of a 3D choroid plexus organoid

University Of North Dakota, Grand Forks ND

Investigators

Abstract

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. The choroid plexus is a highly vascularized tissue within the ventricles of the brain and is responsible for production of cerebral spinal fluid. The epithelial cells of the choroid plexus form tight junctions, comprising the blood-CSF barrier (BCSFB). Some pathogens can disrupt this barrier and thus the choroid plexus can serve as a point of entry into the CNS. We previously published that primary human choroid plexus epithelial cells stimulated with B. burgdorferi induced the production of inflammatory and chemotactic cytokines, and transcriptome analysis revealed reduced expression of genes encoding barrier and scaffolding proteins, suggesting a loss of barrier integrity. We also demonstrated in in a mouse model that infection with B. burgdorferi resulted in perivascular infiltrates and hemorrhage around blood vessels of the choroid plexus. In new preliminary data, we now demonstrate the presence of B. burgdorferi in the CSF of mice. We hypothesize that B. burgdorferi can exploit the choroid plexus and the BCSFB to invade the CNS. Our Aim in this proposal is to establish a human choroid plexus organoid system and test its feasibility as a model for studying the choroid plexus’ role in Lyme neuroborreliosis. Our proposal directly addresses the NIH Strategic Plan for Tickborne Disease Research, including understanding host interactions with tickborne pathogens. Development of the choroid plexus organoid will allow us to: examine interactions between different B. burgdorferi genospecies and mutants and the choroid plexus; identify bacterial factors necessary and sufficient for CNS invasion; and measure the effect of B. burgdorferi on tight junctions and barrier function in the absence of the added complexity of host immune factors. This model will be a useful screening tool to identify bacterial factors involved in neurotropism prior to more complex studies in immunocompetent animal models.