Extravasation of Borrelia burgdorferi Across the Blood–Brain Barrier is an Extremely Rare Event

Abstract Lyme disease, the most widespread tick‐borne disease in North America, is caused by the bacterium Borrelia burgdorferi ( Bb ). Approximately 10–15% of infections result in neuroborreliosis, common symptoms of which include headaches, facial palsy, and long‐term cognitive impairment. Previous studies of Bb dissemination focus on assessing Bb transmigration at static time points rather than analyzing the complex dynamic process of extravasation. Furthermore, current in vitro models lack crucial physiological factors such as flow, demonstrating a need for more robust models for studying Bb dissemination to understand its dynamics and mechanisms. Here, a 3D tissue‐engineered microvessel model is used and fluorescently‐labeled Bb is perfused to model vascular dissemination in non‐tissue‐specific (iEC) and brain‐specific (iBMEC) microvessels while acquiring time‐lapse images in real time. In iECs, extravasation involves two steps: adhesion to the endothelium and transmigration into the extracellular matrix, which can be modulated through glycocalyx degradation or inflammation. In contrast, Bb extravasation in iBMECs is an extremely rare event regardless of glycocalyx degradation or inflammation. In addition, circulating Bb do not induce endothelial activation in iECs or iBMECs, but induces barrier dysfunction in iECs. These findings provide a further understanding of Bb vascular dissemination.