Yersinia pestis, a Gram-negative bacterium and the etiologic agent of plague, has evolved from Yersinia pseudotuberculosis, a cause of a mild enteric disease. However, the molecular and biological mechanisms of how Y pseudotuberculosis evolved to such a remarkably virulent pathogen, Y pestis, are not clear. The ability to initiate a rapid bacterial dissemination is a characteristic hallmark of Y pestis infection. A distinguishing characteristic between the two Yersinia species is that Y pseudotuberculosis strains possess an O-antigen of lipopolysaccharide (LPS) while Y pestis has lost the O-antigen during evolution and therefore exposes its core LPS. In this study, we showed that Y pestis utilizes its core LPS to interact with SIGNR1 (CD209b), a C-type lectin receptor on antigen presenting cells (APCs), leading to bacterial dissemination to lymph nodes, spleen and liver, and the initiation of a systemic infection. We therefore propose that the loss of O-antigen represents a critical step in the evolution of Y pseudotuberculosis into Y pestis in terms of hijacking APCs, promoting bacterial dissemination and causing the plague.