Senior Author: Tara Moriarty, Ph.D.
University of Toronto, Canada
Faculty of Dentistry, Matrix Dynamics Group
Faculty of Medicine, Department of Laboratory Medicine and Pathobiology
Lead Author: Rhodaba Ebady, Ph.D. student
University of Toronto, Canada
Faculty of Dentistry, Matrix Dynamics Group
MedicalResearch.com: What is the background for this study? What are the main findings?
Response: The spread of microbes via the bloodstream (dissemination) is responsible for most of the mortality associated with bacterial infection. Even though this is a clinically important step of many infectious diseases, and likely an important target for disease treatment, we don’t know how most microbes disseminate. One of the key steps in this process is adhesion of bacteria to the inner surfaces of blood vessels. This allows bacteria to slow down enough to grab onto vessel surfaces, then escape from the blood stream into tissues where it’s easier for them to live. It’s a bit like the problem faced by a person being carried down a fast-flowing river who needs to grab onto something on the banks to get out onto dry land. A big problem for bacteria, and any other cells which must stick to blood vessel walls (like white blood cells travelling to a site of infection or inflammation), is that they have to be able to stick to vessel walls without being ripped off by the flow of blood. They have to have adhesion mechanisms strong enough to overcome forces due to flow. It’s also really helpful to be able to hang on but keep moving along walls until they reach a good spot to get out. This is important for white blood cells too, which have to “sample” their environment to get to the right place to get out of blood flow.
Even though the problem of how bacteria stick to blood vessel walls is so important clinically, the mechanisms bacteria use to do this are not widely understood. Part of this gap in our knowledge arises because we haven’t had good tools to study this process as it happens, and to understand how force affects bacterial interaction with vessel walls. The process of bacteria sticking to blood vessel walls is very fast, and hard to observe. The methods to observe this have already been developed, but the major technical innovations of our paper were to figure out how to identify and track the movement of the individual bacteria which stuck to vessel walls among millions flowing past, and to figure out how to set up a flow chamber system which replicated certain conditions in human blood vessels. Figuring out how to do this allowed us to figure out a lot about how the bacteria moved, and the forces and mechanisms involved in adhesion. It took a couple of years just to figure out the common patterns in the thousands of tracks of bacteria interacting with blood vessels, after the initial technical innovation.
The major findings of our study are that, surprisingly, the bacteria which cause Lyme disease, Borrelia burgdorferi, interact with blood vessels using many of the same mechanisms that help white blood cells stick to the same vessel walls. The major similarities between Borrelia and white blood cell interaction mechanisms were that both transfer mechanical load from one adhesion complex to the next during interactions (like a child moving forward along monkey bars by swinging from one hand to the next), that both are stabilized by bungee cord-like tethers which anchor cells to surfaces, and that both use a special kind of bond called a catch bond to stick to the cells lining vessel walls. Catch bonds are different from the conventional bonds which hold molecules together, because conventional bonds are broken really easily when you pull on them, but catch bonds actually get stronger when they’re pulled.
The similarity between the mechanisms used by Borrelia and white blood cells to stick to vessel walls was really surprising, because the shape and physiology of Borrelia and white blood cells are very different, not to mention that they’re far apart in evolution. We think this is because bacteria and cells that are normally present in the blood stream face the same physical problem, which is how to stick to and move along blood vessel surfaces without being ripped off by blood flow.
One of the major findings of our study was also the identification the first bacterial vascular adhesion protein which can act as a catch bond. This protein, BBK32, shares some similarity to adhesion proteins from genetically distant bacteria, so we think there may be some possibility that BBK32-like proteins in other disease-causing bacteria might also be important for adhesion to blood vessel surfaces. We don’t know….there’s a long way to go to test these hypotheses, but it’s certainly pretty exciting!
MedicalResearch.com: What should readers take away from your report?
Response: That Lyme disease Borrelia and white blood cells use similar mechanisms to stick to blood vessel surfaces, and that we have developed methods which will probably be useful for understanding the mechanisms by which many bacteria spread through the blood stream. Since our understanding of how white blood cells stick to these surfaces is much more advanced than our understanding of bacterial dissemination, there may be strategies which have already been developed to target white blood cell adhesion which might be useful for treating bacterial infection. And there may be a whole group of specialized bacterial proteins out there which have catch bond properties that enable bacteria to stick to blood vessel walls. We hope that the methods we’ve developed will allow a lot of researchers to begin studying this clinically important problem for multiple diseases, not just Lyme disease.
MedicalResearch.com: What recommendations do you have for future research as a result of this study?
Response: There’s so much to do that it’s hard to recommend anything specific. Every group working on this topic with a different bacterial pathogen will have different directions to pursue. However, in our lab, we’re working on understanding how components of the blood contribute to B. burgdorferi adheres to blood vessel surfaces, the mechanisms which promote B. burgdorferi interactions with blood vessels from different tissues (since this will likely determine which tissues the bacteria can spread to and infect). We’re also trying to map the parts of BBK32 which give it force-strengthened catch bond properties, so that ultimately, we can try to identify molecules or strategies which block this protein’s ability to strengthen bacteria interactions with blood vessel walls.
MedicalResearch.com: Is there anything else you would like to add?
Response: That the monumental amount of work for this paper was primarily completed by a talented, hard-working team of graduate and undergraduate students, as well as collaborators from the labs of Craig Simmons and Jon Skare. The primary author on this paper is Ph.D. student Rhodaba Ebady, the second author Alex Niddam was another major contributor, and co-authors Anna Boczula, Yae-Ram Kim, Nupur Gupta, Tian Tian Tang, Tanya Odisho (all from the Moriarty lab), and Hui Zhi from the Skare lab worked really hard, and in some cases over many years to make this project work.
Ebady et al. Biomechanics of Borrelia burgdorferi Vascular Interactions. Cell Reports, 2016 DOI:10.1016/j.celrep.2016.08.013
Readers who would like to know more about our work can find us through:
Our lab website http://moriartylab.org
Lab YouTube channel: https://www.youtube.com/channel/UCeEAjkGzgd9HtDKXzr_dXOg
Note: Content is Not intended as medical advice. Please consult your health care provider regarding your specific medical condition and questions.
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