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Plague, initiated by  Yersinia pestis  infection, is a rapidly progressing disease with a high mortality rate if not quickly treated. The existence of antibiotic-resistant  Y. pestis  strains emphasizes the need for the development of novel countermeasures against plague. We previously reported the generation of a recombinant  Y. pestis  strain (Kim53ΔJ+P) that over-expresses  Y .  enterocolitica  YopP. When this strain was administered subcutaneously to mice, it elicited a fast and effective protective immune response in models of bubonic, pneumonic and septicemic plague. In the present study, we further characterized the immune response induced by the Kim53ΔJ+P recombinant strain. Using a panel of mouse strains defective in specific immune functions, we observed the induction of a prompt protective innate immune response that was interferon-γ dependent. Moreover, inoculation of mice with  Y. pestis  Kim53ΔJ+P elicited a rapid protective response against secondary infection by other bacterial pathogens, including the enteropathogen  Y .  enterocolitica  and the respiratory pathogen  Francisella tularensis.  Thus, the development of new therapies to enhance the innate immune response may provide an initial critical delay in disease progression following the exposure to highly virulent bacterial pathogens, extending the time window for successful treatment.

YopP-Expressing Variant of Y. pestis Activates a Potent Innate Immune Response Affording Cross-Protection against Yersiniosis and Tularemia