The Role and Mechanism of Erythrocyte Invasion by Francisella tularensis

is an extremely virulent bacterium that can be transmitted naturally by blood sucking arthropods. During mammalian infection, infects numerous types of host cells, including erythrocytes. As erythrocytes do not undergo phagocytosis or endocytosis, it remains unknown how invades these cells. Furthermore, the consequence of inhabiting the intracellular space of red blood cells (RBCs) has not been determined. Here, we provide evidence indicating that residing within an erythrocyte enhances the ability of to colonize ticks following a blood meal. Erythrocyte residence protected from a low pH environment similar to that of gut cells of a feeding tick. Mechanistic studies revealed that the type VI secretion system (T6SS) was required for erythrocyte invasion as mutation of (a transcriptional regulator of T6SS genes), , or (two genes encoding T6SS machinery) severely diminished bacterial entry into RBCs. Invasion was also inhibited upon treatment of erythrocytes with venom from the Blue-bellied black snake ( ), which aggregates spectrin in the cytoskeleton, but not inhibitors of actin polymerization and depolymerization. These data suggest that erythrocyte invasion by is dependent on spectrin utilization which is likely mediated by effectors delivered through the T6SS. Our results begin to elucidate the mechanism of a unique biological process facilitated by to invade erythrocytes, allowing for enhanced colonization of ticks.