title: D27-pLpxL, an avirulent strain of Yersinia pestis, primes T cells that protect against pneumonic plague.
abstract: 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 muMT 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 CD44(high) CD43(high) 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.
authors.affiliation: Trudeau Institute, Saranac Lake, New York 12983, USA.
authors.forename: Frank M
authors.initials: FM
authors.lastname: Szaba
authors.forename: Lawrence W
authors.initials: LW
authors.lastname: Kummer
authors.forename: Lindsey B
authors.initials: LB
authors.lastname: Wilhelm
authors.forename: Jr-Shiuan
authors.initials: JS
authors.lastname: Lin
authors.forename: Michelle A
authors.initials: MA
authors.lastname: Parent
authors.forename: Sara W
authors.initials: SW
authors.lastname: Montminy-Paquette
authors.forename: Egil
authors.initials: E
authors.lastname: Lien
authors.forename: Lawrence L
authors.initials: LL
authors.lastname: Johnson
authors.forename: Stephen T
authors.initials: ST
authors.lastname: Smiley
mesh_terms: D000217:Acyltransferases / Q000096:biosynthesis* / Q000235:genetics; D000281:Administration, Intranasal; D000818:Animals; D001428:Bacterial Vaccines / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology*; D015169:Colony Count, Microbial; D029968:Escherichia coli Proteins / Q000096:biosynthesis* / Q000235:genetics; D005260:Female; D018960:Hyaluronan Receptors / Q000032:analysis; D007371:Interferon-gamma / Q000096:biosynthesis; D051917:Leukosialin / Q000032:analysis; D008099:Liver / Q000276:immunology / Q000382:microbiology / Q000473:pathology; D008168:Lung / Q000276:immunology / Q000382:microbiology / Q000473:pathology; D008213:Lymphocyte Activation; D008297:Male; D051379:Mice; D010930:Plague / Q000276:immunology / Q000517:prevention & control*; D011994:Recombinant Proteins / Q000096:biosynthesis / Q000235:genetics; D016019:Survival Analysis; D016176:T-Lymphocyte Subsets / Q000737:chemistry / Q000276:immunology; D013601:T-Lymphocytes / Q000737:chemistry / Q000276:immunology* / Q000382:microbiology*; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis; D014613:Vaccines, Attenuated / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology; D015010:Yersinia pestis / Q000235:genetics / Q000276:immunology*
chemical_list: D001428:Bacterial Vaccines; C476399:Cd44 protein, mouse; D029968:Escherichia coli Proteins; D018960:Hyaluronan Receptors; D051917:Leukosialin; D011994:Recombinant Proteins; C497863:Spn protein, mouse; D014409:Tumor Necrosis Factor-alpha; D014613:Vaccines, Attenuated; D007371:Interferon-gamma; D000217:Acyltransferases; C492237:LpxL protein, E coli