Borrelia burgdorferi, Host-Derived Proteases, and the Blood-Brain Barrier
Dennis J. Grab,1,* George Perides,2 J. Stephen Dumler,3 Kee Jun Kim,1 Jinho Park,3 Yuri V. Kim,1 Olga Nikolskaia,1 Kyoung Seong Choi,3 Monique F. Stins,1 and Kwang Sik Kim1
2005
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC546937/
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DISCUSSION
The neurological manifestations of Lyme disease in humans caused by B. burgdorferi are attributed in part to penetration of the CNS by spirochetes, yet how the Lyme disease spirochetes cross the BBB remains an understudied and unresolved issue. B. burgdorferi freely crosses nonbrain vascular endothelium (13, 57, 88, 90). Our knowledge concerning how this occurs stems from in vitro studies that examined the ability of the spirochetes to bind to and cross confluent vascular endothelial cell monolayers in vitro (13, 57, 88, 90). After the initial binding event, how the spirochetes cross vascular endothelium (paracellular versus transcellular) remains controversial. By using electron microscopy, Comstock and Thomas (13) first demonstrated that B. burgdorferi spirochetes are able to enter and translocate across the cytoplasm of HUVEC grown on polycarbonate filters (Nuclepore inserts), a process that requires intact viable cells and bacteria (13, 57). The spirochetes were first observed to cross by dark-field microscopy as early as 2 h, and almost 8% of the added bacteria crossed by 4 h (13). Low-passage B. burgdorferi isolates adhere to HUVEC up to 30-fold more than spirochetes maintained continuously in culture adhere to HUVEC (88). While adherence to and transcellular crossing of endothelial cells is both time and inoculum dependent (13, 57, 90, 91), not all studies have supported a transcellular route of crossing. For example, Szczepanski et al. (88) cited the presence of B. burgdorferi in the intercellular junctions between endothelial cells, as well as beneath the monolayers, as evidence that spirochetes actually pass between the cells. More spirochetes crossed the barrier when the monolayers were pretreated with EDTA that was used to lower the TEER of the endothelial cell barrier (88). It is of related interest that Treponema pallidum, the causative agent of syphilis, also migrates across endothelial cell monolayers at intercellular junctions (89).
In spite of these investigations of B. burgdorferi-endothelial cell interactions, no study has been conducted to examine the interactions of these bacteria with brain microvascular endothelial cells (the functional unit of the BBB), an in vitro BBB model that has been used to study the transmigration of monocytes, neutrophils, bacteria, fungi, and African trypanosomes (17, 28, 29, 32, 36, 37, 38, 62, 66, 70, 74). Our data show that B. burgdorferi spirochetes differentially cross human BMEC and HUVEC and that the human BMEC form a barrier to traversal by B. burgdorferi. If spirochetes are able to cross human BMEC as easily as they cross systemic nonbrain endothelium, one might expect an earlier and/or far higher incidence of CNS involvement, observations not supported by the clinical findings that have been described. HUVEC lack the tight junctional complex that is key to BMEC's function as a barrier to pathogen entry into the brain. From a comparative viewpoint, it is also interesting that while Szczepanski et al. (88) observed that ≥22-fold more low-passage B. burgdorferi than high-passage spirochetes adhered and crossed HUVEC, we found that about 21-fold more low-passage Borrelia crossed HUVEC than crossed human BMEC. This finding also underscores the concept that one cannot extrapolate data concerning B. burgdorferi penetration of the BBB from experimental data based on nonbrain vascular endothelial cell models.
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