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Infection and Immunity, October 2009, p. 4295-4304, Vol. 77, No. 10
0019-9567/09/$08.00+0     doi:10.1128/IAI.00273-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

D27-pLpxL, an Avirulent Strain of Yersinia pestis, Primes T Cells That Protect against Pneumonic Plague{triangledown}

Frank M. Szaba,1,{dagger} Lawrence W. Kummer,1,{dagger} Lindsey B. Wilhelm,1 Jr-Shiuan Lin,1 Michelle A. Parent,2 Sara W. Montminy-Paquette,3 Egil Lien,3 Lawrence L. Johnson,1 and Stephen T. Smiley1*

Trudeau Institute, Saranac Lake, New York 12983,1 University of Delaware, Newark, Delaware 19716,2 University of Massachusetts Medical School, Department of Medicine, Division of Infectious Diseases and Immunology, Worcester, Massachusetts 016053

Received 9 March 2009/ Returned for modification 9 April 2009/ Accepted 14 July 2009

Vaccinating with live, conditionally attenuated, pigmentation (Pgm)-deficient Yersinia pestis primes T cells that protect mice against pneumonic plague. However, Pgm-deficient strains are not considered safe for human use because they retain substantial virulence in animal models. Y. pestis strains engineered to express Escherichia coli LpxL are avirulent owing to constitutive production of lipopolysaccharide with increased Toll-like receptor 4-activating ability. We generated an LpxL-expressing Pgm-deficient strain (D27-pLpxL) and demonstrate here that this avirulent strain retains the capacity to prime protective T cells. Compared with unvaccinated controls, mice immunized intranasally with live D27-pLpxL exhibit a decreased bacterial burden and increased survival when challenged intranasally with virulent Y. pestis. T cells provide a substantial degree of this protection, as vaccine efficacy is maintained in B-cell-deficient µMT mice unless those animals are depleted of CD4 and CD8 T cells at the time of challenge. Upon challenge with Y. pestis, pulmonary T-cell numbers decline in naive mice, whereas immunized mice show increased numbers of CD44high CD43high effector T cells and T cells primed to produce tumor necrosis factor alpha and gamma interferon; neutralizing these cytokines at the time of challenge abrogates protection. Immunization does not prevent dissemination of Y. pestis from the lung but limits bacterial growth and pathology in visceral tissue, apparently by facilitating formation of granuloma-like structures. This study describes a new model for studying T-cell-mediated protection against pneumonic plague and demonstrates the capacity for live, highly attenuated, Y. pestis vaccine strains to prime protective memory T-cell responses safely.

* Corresponding author. Mailing address: 154 Algonquin Avenue, Saranac Lake, NY 12983. Phone: (518) 891-3080. Fax: (518) 891-5126. E-mail: ssmiley{at}trudeauinstitute.org

{triangledown} Published ahead of print on 20 July 2009.

Editor: J. B. Bliska

{dagger} These authors contributed equally.

Infection and Immunity, October 2009, p. 4295-4304, Vol. 77, No. 10
0019-9567/09/$08.00+0     doi:10.1128/IAI.00273-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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