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Characterization of the Burkholderia mallei tonB Mutant and Its Potential as a Backbone Strain for Vaccine Development.

Mott TM, Vijayakumar S, Sbrana E, Endsley JJ, Torres AG - PLoS Negl Trop Dis (2015)

Bottom Line: At 21 days post-immunization, TMM001-treated animals showed significantly higher levels of B. mallei-specific IgG1, IgG2a and IgM when compared to PBS-treated controls.At 48 h post-challenge, PBS-treated controls exhibited higher levels of serum inflammatory cytokines and more severe pathological damage to target organs compared to animals receiving TMM001.Although further work is needed to prevent chronic infection by TMM001 while maintaining immunogenicity, our attenuated strain demonstrates great potential as a backbone strain for future vaccine development against both glanders and melioidosis.

View Article: PubMed Central - PubMed

Affiliation: Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, Texas, United States of America.

ABSTRACT

Background: In this study, a Burkholderia mallei tonB mutant (TMM001) deficient in iron acquisition was constructed, characterized, and evaluated for its protective properties in acute inhalational infection models of murine glanders and melioidosis.

Methodology/principal findings: Compared to the wild-type, TMM001 exhibits slower growth kinetics, siderophore hyper-secretion and the inability to utilize heme-containing proteins as iron sources. A series of animal challenge studies showed an inverse correlation between the percentage of survival in BALB/c mice and iron-dependent TMM001 growth. Upon evaluation of TMM001 as a potential protective strain against infection, we found 100% survival following B. mallei CSM001 challenge of mice previously receiving 1.5 x 10(4) CFU of TMM001. At 21 days post-immunization, TMM001-treated animals showed significantly higher levels of B. mallei-specific IgG1, IgG2a and IgM when compared to PBS-treated controls. At 48 h post-challenge, PBS-treated controls exhibited higher levels of serum inflammatory cytokines and more severe pathological damage to target organs compared to animals receiving TMM001. In a cross-protection study of acute inhalational melioidosis with B. pseudomallei, TMM001-treated mice were significantly protected. While wild type was cleared in all B. mallei challenge studies, mice failed to clear TMM001.

Conclusions/significance: Although further work is needed to prevent chronic infection by TMM001 while maintaining immunogenicity, our attenuated strain demonstrates great potential as a backbone strain for future vaccine development against both glanders and melioidosis.

No MeSH data available.


Related in: MedlinePlus

TMM001 provides increased protection against B. pseudomallei wild-type challenge.Mice were immunized i.n. with PBS (solid triangle) (n = 7) or 1.5 x 104 CFU (solid circle) of TMM001 (n = 8). Three weeks later, BALB/c mice were challenged (day 0) with 9.36 x 102 CFU of B. pseudomallei K96243. Statistically significant differences in survival times were determined by Kaplan-Meier curves, followed by a log rank test. ★★★ p ≤ 0.0001.
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pntd.0003863.g008: TMM001 provides increased protection against B. pseudomallei wild-type challenge.Mice were immunized i.n. with PBS (solid triangle) (n = 7) or 1.5 x 104 CFU (solid circle) of TMM001 (n = 8). Three weeks later, BALB/c mice were challenged (day 0) with 9.36 x 102 CFU of B. pseudomallei K96243. Statistically significant differences in survival times were determined by Kaplan-Meier curves, followed by a log rank test. ★★★ p ≤ 0.0001.

Mentions: We next tested TMM001 for its protective potential against B. pseudomallei in an acute inhalational model of murine melioidosis. Mice received 1.5 x 104 CFU of TMM001 and at 21 days post-immunization, they were challenged with 9.0 x 102 CFU (3 LD50) of B. pseudomallei strain K96243 [26]. All PBS-treated BALB/c mice died by day 5 post-challenge and displayed a median survival of 5 days (Fig 8). In mice immunized with TMM001, survival was increased to 75% (★★★, p ≤ 0.001) at the end point of 36 days. As with the previous B. mallei study described above, the TMM001 strain, but not the wild-type B. pseudomallei, were recovered from immunized mice who presented with splenomegaly accompanied by abscesses.


Characterization of the Burkholderia mallei tonB Mutant and Its Potential as a Backbone Strain for Vaccine Development.

Mott TM, Vijayakumar S, Sbrana E, Endsley JJ, Torres AG - PLoS Negl Trop Dis (2015)

TMM001 provides increased protection against B. pseudomallei wild-type challenge.Mice were immunized i.n. with PBS (solid triangle) (n = 7) or 1.5 x 104 CFU (solid circle) of TMM001 (n = 8). Three weeks later, BALB/c mice were challenged (day 0) with 9.36 x 102 CFU of B. pseudomallei K96243. Statistically significant differences in survival times were determined by Kaplan-Meier curves, followed by a log rank test. ★★★ p ≤ 0.0001.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4482651&req=5

pntd.0003863.g008: TMM001 provides increased protection against B. pseudomallei wild-type challenge.Mice were immunized i.n. with PBS (solid triangle) (n = 7) or 1.5 x 104 CFU (solid circle) of TMM001 (n = 8). Three weeks later, BALB/c mice were challenged (day 0) with 9.36 x 102 CFU of B. pseudomallei K96243. Statistically significant differences in survival times were determined by Kaplan-Meier curves, followed by a log rank test. ★★★ p ≤ 0.0001.
Mentions: We next tested TMM001 for its protective potential against B. pseudomallei in an acute inhalational model of murine melioidosis. Mice received 1.5 x 104 CFU of TMM001 and at 21 days post-immunization, they were challenged with 9.0 x 102 CFU (3 LD50) of B. pseudomallei strain K96243 [26]. All PBS-treated BALB/c mice died by day 5 post-challenge and displayed a median survival of 5 days (Fig 8). In mice immunized with TMM001, survival was increased to 75% (★★★, p ≤ 0.001) at the end point of 36 days. As with the previous B. mallei study described above, the TMM001 strain, but not the wild-type B. pseudomallei, were recovered from immunized mice who presented with splenomegaly accompanied by abscesses.

Bottom Line: At 21 days post-immunization, TMM001-treated animals showed significantly higher levels of B. mallei-specific IgG1, IgG2a and IgM when compared to PBS-treated controls.At 48 h post-challenge, PBS-treated controls exhibited higher levels of serum inflammatory cytokines and more severe pathological damage to target organs compared to animals receiving TMM001.Although further work is needed to prevent chronic infection by TMM001 while maintaining immunogenicity, our attenuated strain demonstrates great potential as a backbone strain for future vaccine development against both glanders and melioidosis.

View Article: PubMed Central - PubMed

Affiliation: Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, Texas, United States of America.

ABSTRACT

Background: In this study, a Burkholderia mallei tonB mutant (TMM001) deficient in iron acquisition was constructed, characterized, and evaluated for its protective properties in acute inhalational infection models of murine glanders and melioidosis.

Methodology/principal findings: Compared to the wild-type, TMM001 exhibits slower growth kinetics, siderophore hyper-secretion and the inability to utilize heme-containing proteins as iron sources. A series of animal challenge studies showed an inverse correlation between the percentage of survival in BALB/c mice and iron-dependent TMM001 growth. Upon evaluation of TMM001 as a potential protective strain against infection, we found 100% survival following B. mallei CSM001 challenge of mice previously receiving 1.5 x 10(4) CFU of TMM001. At 21 days post-immunization, TMM001-treated animals showed significantly higher levels of B. mallei-specific IgG1, IgG2a and IgM when compared to PBS-treated controls. At 48 h post-challenge, PBS-treated controls exhibited higher levels of serum inflammatory cytokines and more severe pathological damage to target organs compared to animals receiving TMM001. In a cross-protection study of acute inhalational melioidosis with B. pseudomallei, TMM001-treated mice were significantly protected. While wild type was cleared in all B. mallei challenge studies, mice failed to clear TMM001.

Conclusions/significance: Although further work is needed to prevent chronic infection by TMM001 while maintaining immunogenicity, our attenuated strain demonstrates great potential as a backbone strain for future vaccine development against both glanders and melioidosis.

No MeSH data available.


Related in: MedlinePlus