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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.In a cross-protection study of acute inhalational melioidosis with B. pseudomallei, TMM001-treated mice were significantly protected.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.In a cross-protection study of acute inhalational melioidosis with B. pseudomallei, TMM001-treated mice were significantly protected.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