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Inhalational anthrax is initiated by pulmonary exposure to Bacillus anthracis spores. Spore entry into lung epithelial cells is observed both in vitro and in vivo and evidence suggests it is important for bacterial dissemination and virulence. However the specific host receptor and spore factor that mediate the entry process were unknown. Here, we report that integrin α2β1 is a major receptor for spore entry. This is supported by results from blocking antibodies, siRNA knock-down, colocalization, and comparison of spore entry into cells that do or do not express α2. BclA, a major spore surface protein, is found to be essential for entry and α2β1-mediated entry is dependent on BclA. However, BclA does not appear to bind directly to α2. Furthermore, spore entry into α2-expressing cells is dramatically reduced in the absence of serum, suggesting that additional factors are involved. Finally, complement component C1q, also an α2β1 ligand, appears to act as a bridging molecule or a cofactor for BclA/α2β1-mediated spore entry and BclA binds to C1q in a dose-dependent and saturable manner. These findings suggest a novel mechanism for pathogen entry into host cells as well as a new function for C1q-integrin interactions. The implications of these findings are discussed. [ABSTRACT FROM AUTHOR]