How Lyme Disease Bacteria Migrate Through Blood Vessels
A recent study has shown that Borrelia burgdorferi, the bacterium that causes Lyme disease, spreads throughout the body by crawling along the inside wall—the endothelium—of blood vessels.
A recent study has shown that Borrelia burgdorferi, the bacterium that causes Lyme disease, spreads throughout the body by crawling along the inside wall—the endothelium—of blood vessels. Rhodaba Ebady, University of Toronto, Ontario, Canada, and colleagues published the results of their study in Cell Reports, showing that the bacterium moves along the endothelium using a mechanism that is similar to the one used by leukocytes—the body’s white blood cells—as they migrate to sites of inflammation within the body. With the help of the bacterial protein BBK32, B. burgdorferi repeatedly attaches to the endothelium and then detaches from it, allowing the bacterium to use a grab-and-release mechanism to travel along the blood vessel wall without being swept away by the blood.
The findings of this study have “provided insight into physical mechanisms of bacterial-endothelial interactions, and revealed remarkable similarities in the mechanisms by which bacteria and leukocytes interact with and move over endothelial surfaces, including dependence on tethers and catch bonds,” the authors write.
As they migrate within blood vessels to sites of inflammation, leukocytes collide with red blood cells and become pushed peripherally to the endothelial surface. Leukocytes attach transiently to the endothelium, detach, and then bind again, allowing them to move along it by a process known as rolling. This interaction between leukocytes and the blood vessel wall is stabilized by tethers, which are cellular and extracellular structures that facilitate the attachment. For example, elastic membrane tethers extruded from leukocytes serve to anchor the cells to the blood vessel wall. These tethers serve as bungee cord-like structures that balance out the force placed on the bonds. They stretch as the leukocyte moves along the vessel wall, preventing the cells from completely detaching.
In addition, noncovalent bonds known as catch bonds also help to stabilize the interaction. These bonds actually strengthen when force is applied to them, allowing the attachment to last longer and the detachment to occur more slowly above certain stress and force thresholds. According to Ebady and colleagues, although tethers and catch bonds can independently stabilize leukocyte rolling under lower shear stress conditions, they also act together to strengthen interactions at higher shear stresses.
“Bacteria circulating in the bloodstream face the same mechanical barriers to vascular adhesion and extravasation as circulating host cells, but the physical mechanisms permitting their adhesion to vascular surfaces under physiological shear stress are largely unknown,” the authors add.
With this in mind, Ebady and colleagues developed a live-cell imaging system to investigate how B. burgdorferi use blood vessels to spread throughout the body, in order to reach tissues and organs where they can persist and avoid the effects of Lyme disease treatments. Even after appropriate antibiotic treatment, up to 20% of patients with Lyme disease develop post-treatment Lyme disease syndrome and continue to experience long term symptoms, including fatigue, joint and muscle pain, and problems with memory or concentration. Although controversial, some experts suspect this arises because B. burgdorferi persists in some patients, even after treatment.
In their study, the researchers performed flow chamber experiments under controlled shear stress to examine real-time interactions between the bacterium and endothelium. They also used particle tracking methods to examine the interactions in blood vessels of live mice. In the flow chamber system, the researchers tagged the B. burgdorferi bacterium with a fluorescent marker, in order to use a microscope to more easily follow its movement along the vessel.
Their experiments showed that the bacterium not only uses the bacterial protein BBK32 to form catch bonds with the endothelium, but also that it uses tethers to stabilize and strengthen these bonds. They found that the bacteria can travel along the endothelium without detaching, by transferring mechanical force from one catch bond to the next, as these bonds are successively formed and broken; the bacteria slowed down whenever they formed a new bond with the endothelium, and then accelerated as they broke a bond and moved on to form a new one.
The researchers also showed that the force produced by bacterial motility (by virtue of bacterial flagella) was greater than the force that blood flow placed on bonds between the bacteria and endothelium during most interactions. This suggests that the bacteria can overcome the force of the blood flow, using their flagella to control where they leave a blood vessel to infect certain tissues.
Overall, these studies show that B. burgdorferi interacts with endothelial surfaces in a similar way to how leukocytes interact with endothelial surfaces. “We propose that catch bonds and tethering are common cellular responses to the universal problem of vascular adhesion under shear stress, and likely facilitate dissemination of other extracellular pathogens,” the authors conclude.