OspA-CD40 dyad: ligand-receptor interaction in the translocation of neuroinvasive Borrelia across the blood-brain barrier

Abstract

Lyme borreliosis is the most widespread vector-borne disease in temperate zones of Europe and North America. Although the infection is treatable, the symptoms are often overlooked resulting in infection of the neuronal system. In this work we uncover the underlying molecular mechanism of borrelial translocation across the blood-brain barrier (BBB). We demonstrate that neuroinvasive strain of Borrelia readily crosses monolayer of brain-microvascular endothelial cells (BMECs) in vitro and BBB in vivo. Using protein-protein interaction assays we found that CD40 of BMECs and OspA of Borrelia are the primary molecules in transient tethering of Borrelia to endothelium. OspA of neuroinvasive Borrelia, but not of non-neuroinvasive strain, binds CD40. Furthermore, only the neuroinvasive Borrelia and its recombinant OspA activated CD40-dependent pathway in BMECs and induced expression of integrins essential for stationary adhesion. Demonstration of the CD40-ligand interactions may provide a new possible perspective on molecular mechanisms of borrelial BBB translocation process.

Structure et mode d’injection de l’oncoprotéine CagA d’Helicobacter pylori

“…[5][6][7]. Les cellules LLC-B ont un métab olisme plus actif que les cellules saines, ce qui entraîne une production plus importante de radicaux libres et une dépendance vis-à-vis des antioxydants cellulaires comme le glutathion (GSH) pour maintenir leur balance redox intracellulaire [8,9]. De plus, l'interaction des cellules LLC-B avec les cellules accessoires (cellules stromales, cellules nurse-like) dans la moelle osseuse ou les ganglions est aussi importante pour leur survie [10,11].…”

Lipoproteins and Diseases of the Brain

“…OspA from B. burgdorferi is able to cross the BBB by binding to CD40 of brain-microvascular endothelial cells [4]. OspA in the brain activates TLR2 on microglia and astrocytes, which initiates immune activity and causes damage to brain tissue [14,50].…”

“…Lipoproteins in the brain are involved in the onset and progression of neurodegenerative diseases (e.g., Alzheimer's disease) [1,2] and neuroinflammatory disorders (e.g., neuroborreliosis) [3,4]. These lipoproteins are either endogenously expressed by astrocytes [5] and microglia [6,7] or exogenously produced by bacterial pathogens (e.g., Borrelia burgdorferi, Streptococcus pneumoniae) [8].…”

“…B. burgdorferi causes Lyme disease, which is the most common tick-borne infection in Europe and in North America [14]. A recent study using rats infected with B. burgdorferi demonstrated that B. burgdorferi was observed across the blood-brain barrier (BBB) and that the expression level of ospA was augmented significantly in the brain [4].…”

Design, construction and evaluation of multi-epitope antigens for diagnosis of Lyme disease

“…The antigen-specific antibodies were affinity purified, as described previously [9]. Briefly, pre-swollen CNBrSepharose 4B beads (Pharmacia Fine Chemicals) were mixed with purified his-tagged OspA or OspC proteins of SKT-2, SKT-4 and SKT-7.1 (previously produced in the author's laboratory [9,13]). Total IgGs (previously purified in the author's laboratory [9]) were incubated with beads for 3 hrs at room temperature, and antigen-specific antibodies eluted from the beads with 3.6M MgCl 2 .…”