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Infection and Immunity, October 2009, p. 4314-4326, Vol. 77, No. 10
0019-9567/09/$08.00+0     doi:10.1128/IAI.00654-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Vaccination with an Attenuated Strain of Francisella novicida Prevents T-Cell Depletion and Protects Mice Infected with the Wild-Type Strain from Severe Sepsis{triangledown} ,{dagger}

Jyotika Sharma, Qun Li, Bibhuti B. Mishra, Michelle J. Georges, and Judy M. Teale*

South Texas Center for Emerging Diseases and Department of Biology, University of Texas at San Antonio, One UTSA Circle, San Antonio, Texas 78249-1644

Received 9 June 2009/ Returned for modification 9 July 2009/ Accepted 16 July 2009

Francisella tularensis is the causative agent of zoonotic tularemia, a severe pneumonia in humans, and Francisella novicida causes a similarly severe tularemia in mice upon inhalation. The correlates of protective immunity, as well as the virulence mechanisms of this deadly pathogen, are not well understood. In the present study, we compared the host immune responses of lethally infected and vaccinated mice to highlight the host determinants of protection from this disease. Intranasal infection with an attenuated mutant (Mut) of F. novicida lacking a 58-kDa hypothetical protein protected C57BL/6 mice from a subsequent challenge with the fully virulent wild-type strain U112 via the same route. The protection conferred by Mut vaccination was associated with reduced bacterial burdens in systemic organs, as well as the absence of bacteremia. Also, there was reduced lung pathology and associated cell death in the lungs of vaccinated mice. Both vaccinated and nonvaccinated mice displayed an initial 2-day delay in upregulation of signature inflammatory mediators after challenge. Whereas the nonvaccinated mice developed severe sepsis characterized by hypercytokinemia and T-cell depletion, the vaccinated mice displayed moderated cytokine induction and contained increased numbers of {alpha}β T cells. The recall response in vaccinated mice consisted of a characteristic Th1-type response in terms of cytokines, as well as antibody isotypes. Our results show that a regulated Th1 type of cell-mediated and humoral immunity in the absence of severe sepsis is associated with protection from respiratory tularemia, whereas a deregulated host response leading to severe sepsis contributes to mortality.

* Corresponding author. Mailing address: South Texas Center for Emerging Diseases and Department of Biology, University of Texas at San Antonio, One UTSA Circle, San Antonio, TX 78249-1644. Phone: (210) 458-7024. Fax: (210) 458-7025. E-mail: judy.teale{at}utsa.edu

{triangledown} Published ahead of print on 27 July 2009.

{dagger} Supplemental material for this article may be found at http://iai.asm.org/.

Editor: A. J. Bäumler

Infection and Immunity, October 2009, p. 4314-4326, Vol. 77, No. 10
0019-9567/09/$08.00+0     doi:10.1128/IAI.00654-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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