Leukocyte guidance and gradient interpretation in vivo

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Our immune system is designed to protect us from infections. For any immune response to occur, white blood cells (leukocytes) need to exit the blood stream and then navigate within tissues in order to find and eliminate invading microbes. This process absolutely relies on their ability to accurately interpret guidance signals produced within tissues. Any malfunction in this process can be the basis of inflammatory diseases (such as allergy, asthma, arthritis and various conditions ending with the suffix '-itis') or insufficient responses to infection (for example in immuno-compromised patients with leukocyte migration defects, such as 'WHIM syndrome' patients). For this reason, manipulating leukocyte navigation for treating inflammatory diseases is a major biomedical target.This target has yet to be met, as we still have little understanding of how leukocytes are guided within the body. Although many types of guidance cues have been identified over the past decades, their actual mode of action and interpretation by leukocytes are poorly understood. If we can understand this, we can be in a much better position of designing effective and selective treatments for inflammatory diseases.I have set up a model system in which we can directly visualize how leukocytes are guided towards infected tissues and dissect the genes and mechanisms that underlie this process. For this I have taken advantage of the zebrafish model, as it is optically transparent, allowing us to easily monitor leukocyte migration, and genetically tractable, allowing us to uncover the underlying genetic mechanisms. Using this unique model system, I have so far discovered that certain guidance cues produced at sites of infection - small proteins called 'chemokines' - need to interact with complex sugars in the tissue environment in order to accurately guide the migration of leukocytes. This has many implications and fundamentally changes our understanding of how chemokines operate. In my proposed plan I intend to elucidate further the mechanism of action of chemokines. We (myself, a research assistant and a team of collaborators with complementary expertise) will investigate how sugars of the tissue environment change the signaling properties of chemokines and how exactly leukocytes process this information into directed movement. We will also expand this approach to other important guidance signals, beyond chemokines. These studies will provide a better understanding of how leukocytes 'read' guidance signals so as to navigate correctly in the body, which can ultimately open new avenues for treating inflammatory diseases.