Anisimov A.P., Shaikhutdinova R.Z., Pan'kina L.N., Feodorova V.A., Savostina E.P.,
Bystrova O.V., Lindner B., Mokrievich A.N., Bakhteeva I.V., Titareva G.M., Dentovskaya S.V., Kocharova N.A.,
Senchenkova S.N., Holst O., Devdariani Z.L., Popov Y.A., Pier G.B., Knirel Y.A. |
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Abstract
Yersinia pestis undergoes an obligate flea-rodent-flea enzootic life cycle. The rapidly fatal properties
of Y. pestis are responsible for the organism's sustained survival in natural plague foci. Lipopolysaccharide
(LPS) plays several roles in Y. pestis pathogenesis, prominent among them being resistance to host immune
effectors and induction of a septic-shock state during the terminal phases of infection. LPS is acylated
with 4-6 fatty acids, the number varying with growth temperature and affecting the molecule's toxic properties.
Y. pestis mutants were constructed with a deletion insertion in the lpxM gene in both virulent and attenuated
strains, preventing the organisms from synthesizing the most toxic hexa-acylated lipid A molecule when grown
at 25 degrees C. The virulence and/or protective potency of pathogenic and attenuated Y. pestis DeltalpxM
mutants were then examined in a mouse model. The DeltalpxM mutation in a virulent strain led to no change
in the LD(50) value compared to that of the parental strain, while the DeltalpxM mutation in attenuated
strains led to a modest 2.5-16-fold reduction in virulence. LPS preparations containing fully hexa-acylated
lipid A were ten times more toxic in actinomycin D-treated mice then preparations lacking this lipid A isoform,
although this was not significant (P>0.05). The DeltalpxM mutation in vaccine strain EV caused a significant
increase in its protective potency. These studies suggest there is little impact from lipid A modifications on
the virulence of Y. pestis strains but there are potential improvements in the protective properties in attenuated
vaccine strains. |
