TY - JOUR
T1 - Yersinia pestis with regulated delayed attenuation as a vaccine candidate to induce protective immunity against plague
AU - Sun, Wei
AU - Roland, Kenneth L.
AU - Kuang, Xiaoying
AU - Branger, Christine G.
AU - Curtiss, Roy
PY - 2010/3
Y1 - 2010/3
N2 - Two mutant strains of Yersinia pestis KIM5+, a Δcrp mutant and a mutant with arabinose-dependent regulated delayed-shutoff crp expression (araC PBAD crp), were constructed, characterized in vitro, and evaluated for virulence, immunogenicity, and protective efficacy in mice. Both strains were highly attenuated by the subcutaneous (s.c.) route. The 50% lethal doses (LD50s) of the Δcrp and araC PBAD crp mutants were approximately 1,000,000-fold and 10,000-fold higher than those of Y. pestis KIM5+, respectively, indicating that both strains were highly attenuated. Mice vaccinated s.c. with 3.8 x 107 CFU of the Δcrp mutant developed high anti-Y. pestis and anti-LcrV serum IgG titers, both with a strong Th2 bias, and induced protective immunity against subcutaneous challenge with virulent Y. pestis (80% survival) but no protection against pulmonary challenge. Mice vaccinated with 3.0 x 104 CFU of the araC PBAD crp mutant also developed high anti-Y. pestis and anti-LcrV serum IgG titers but with a more balanced Th1/Th2 response. This strain induced complete protection against s.c. challenge and partial protection (70% survival) against pulmonary challenge. Our results demonstrate that arabinose-dependent regulated crp expression is an effective strategy to attenuate Y. pestis while retaining strong immunogenicity, leading to protection against the pneumonic and bubonic forms of plague.
AB - Two mutant strains of Yersinia pestis KIM5+, a Δcrp mutant and a mutant with arabinose-dependent regulated delayed-shutoff crp expression (araC PBAD crp), were constructed, characterized in vitro, and evaluated for virulence, immunogenicity, and protective efficacy in mice. Both strains were highly attenuated by the subcutaneous (s.c.) route. The 50% lethal doses (LD50s) of the Δcrp and araC PBAD crp mutants were approximately 1,000,000-fold and 10,000-fold higher than those of Y. pestis KIM5+, respectively, indicating that both strains were highly attenuated. Mice vaccinated s.c. with 3.8 x 107 CFU of the Δcrp mutant developed high anti-Y. pestis and anti-LcrV serum IgG titers, both with a strong Th2 bias, and induced protective immunity against subcutaneous challenge with virulent Y. pestis (80% survival) but no protection against pulmonary challenge. Mice vaccinated with 3.0 x 104 CFU of the araC PBAD crp mutant also developed high anti-Y. pestis and anti-LcrV serum IgG titers but with a more balanced Th1/Th2 response. This strain induced complete protection against s.c. challenge and partial protection (70% survival) against pulmonary challenge. Our results demonstrate that arabinose-dependent regulated crp expression is an effective strategy to attenuate Y. pestis while retaining strong immunogenicity, leading to protection against the pneumonic and bubonic forms of plague.
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U2 - 10.1128/IAI.01122-09
DO - 10.1128/IAI.01122-09
M3 - Article
C2 - 20086087
AN - SCOPUS:77349086332
SN - 0019-9567
VL - 78
SP - 1304
EP - 1313
JO - Infection and immunity
JF - Infection and immunity
IS - 3
ER -