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

Ayelet Zauberman,Avital Tidhar,David Gur,Erez Bar-Haim,Moshe Aftalion,Avigdor Shafferman,Ofer Cohen,Yinon Levy,Gideon Halperin,Yaron Vagima,Yehuda Flashner,Emanuelle Mamroud,Yousef Abu Kwaik

doi:10.1371/journal.pone.0083560

Ayelet Zauberman, Avital Tidhar + Show 11 more

Open Access

https://doi.org/10.1371/journal.pone.0083560

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Journal: PloS one	Publication Date: Dec 16, 2013
Citations: 9	License type: CC BY 4.0

Affiliation: Israel Institute for Biological Research

Abstract

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.

Highlights

Plague is a fatal disease that has caused millions of deaths in three world pandemics, and it remains a public health concern in some regions of the world [1] [2]
Primary pneumonic plague is the more fatal form of the disease, it is less frequent in nature; it results from the inhalation of Y. pestiscontaining droplets or aerosols
We have recently shown that a newly engineered strain of Y. pestis, Kim53DJ+P, is dramatically attenuated in a mouse model of bubonic plague (LD50.107 cfu), whereas its virulence is retained in mouse models of pneumonic and systemic plague [17]

Summary

Introduction

Plague is a fatal disease that has caused millions of deaths in three world pandemics, and it remains a public health concern in some regions of the world [1] [2]. We further characterized the rapid immune response induced by the Kim53DJ+P recombinant Y. pestis strain in an effort to uncover a potential new avenue for the development of protective measures against plague. Consistent with the relatively low specificity characterizing the rapid induction of the innate response, Kim53DJ+P-infected wild-type mice were protected from a lethal challenge with the enteropathogen Y. enterocolitica and with a non-related respiratory pathogen, Francisella tularensis subspecies holarctica LVS.

Results

Conclusion