The mechanism and role of erythrocyte invasion by Francisella tularensis

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Francisella tularensis is one of the most infectious organisms as inhalation of a single bacterium can lead to a fatal disease referred to as tularemia. It has therefore been categorized by the Centers for Disease Control and Prevention as a Category A biodefense agent. Many seminal studies have shown that the ability of F. tularensis to replicate within macrophages is associated with the pathogenesis of this organism. In subsequent years, my laboratory helped to move the field of Francisella research forward by illuminating that interactions with non- macrophages are also extremely important during infection as these cells provide a sanctuary from immunity, allow for bacterial proliferation, and provide protection from antibiotics. Although much of the work in the field of F. tularensis has focused on the intra-macrophage biology of this organism, interactions with other cell types have not been thoroughly investigated. Perhaps the most surprising finding of our laboratory was the discovery that F. tularensis invades and persists in erythrocytes. This invasion enhances the ability of F. tularensis bacteria to survive in ticks (important disease vectors) following a blood meal. In this application, we will test the hypothesis that erythrocyte invasion is required for long-term colonization of ticks and subsequent transmission to mammals. We have previously shown that the erythrocyte surface protein, Band 3 is required for invasion and that interaction with this surface protein may be required for manipulation of the spectrin cytoskeleton through Ankyrin-1. Moreover, we have shown that F. tulareniss bacteria secrete PdpC into erythroyctes via the type VI secretion system (T6SS), and that this effector is required for invasion. OpiA, another T6SS effector, is produced and accumulates in erythrocytes during bacterial persistence. In this application, we will explore these aforementioned host and bacterial proteins to gain insight into the mechanism of erythrocyte invasion and the persistence within these host cells.