The Inverse Relationship Between Cytotoxicity of Y. pestis and Its Virulence

Modulation of host cell death during infection is a prevalent virulence strategy developed by many bacterial pathogens. Yersinia pestis, the causative agent of the fatal plague disease was found to exert limited cytotoxicity towards target immune cells, mediated by type III secretion system effector YopJ. In contrast, the highly cytotoxic closely related Y. enterocolitica O:8 causes a self limited gastrointestinal disease. This phenomenon led us to suggest that the reduced cytotoxic potency of Y. pestis is related to its increased virulence potential. Generation of Y. pestis strain expressing YopP instead of YopJ, enhanced its cytotoxic potency towards macrophages in-vitro and mouse spleen target cells in-vivo. The highly cytotoxic Y. pestis strain demonstrated a reduced ability to colonize internal organs of mice infected subcutaneously, and most strikingly was avirulent in a mouse model of bubonic plague. These results indicate inverse relationship between cytotoxic potency and in-vivo virulence. Still, the same YopP-expressing Y. pestis strain remained fully virulent to mice upon intravenous or intranasal infections, indicating retention of virulence potential. In addition, it was found that subcutaneous administration of the highly cytotoxic Y. pestis strain activated extremely rapid, potent and systemic protective response against concomitant challenges with a virulent strain via the subcutaneous, intravenous or airway routes. These findings may have important implications on the design of future plague vaccine/therapies and contribute to our understanding of virulence strategies of Y. pestis in nature.