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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

Treatment with TMM001 reduces the pro-inflammatory cytokine and chemokine response to B. mallei challenge.Serum cytokine/chemokine profile of PBS- or TMM001-treated mice following exposure to B. mallei CSM001 (1.5x105 CFU) at 0 h (A) and 48 h (B) post challenge. Mean ± SEM plotted are representative of three animals. Statistical significance was determined by one-way ANOVA followed by the Dunnett's test. ★ p ≤ 0.05.
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pntd.0003863.g007: Treatment with TMM001 reduces the pro-inflammatory cytokine and chemokine response to B. mallei challenge.Serum cytokine/chemokine profile of PBS- or TMM001-treated mice following exposure to B. mallei CSM001 (1.5x105 CFU) at 0 h (A) and 48 h (B) post challenge. Mean ± SEM plotted are representative of three animals. Statistical significance was determined by one-way ANOVA followed by the Dunnett's test. ★ p ≤ 0.05.

Mentions: Sera that was collected at 48 h post challenge from PBS- and TMM001-treated mice was used to identify pro-inflammatory cytokine and chemokine responses that correspond with disease outcome. Prior to challenge, a similar baseline expression of cytokines and chemokines was detectable in serum of representative animals from both the PBS- and TMM001-immunized animals (Fig 7A). Following CSM001 challenge, the overall cytokine/chemokine expression increased markedly in both PBS- and TMM001-immunized animals (Fig 7B) compared to baseline, consistent with our previous observations of innate immune responses to Burkholderia species [27]. An attenuation of the pro-inflammatory serum cytokine/chemokine response to challenge was observed in the TMM001-treated compared to PBS control. The reduction of several pro-inflammatory mediators due to TMM001-treatment was significant, including IL-6 (p = 0.049), GM-CSF (p = 0.037), MCP-1 (p = 0.022), and RANTES (p = 0.032) (Fig 7). A trend for reduction of several other pro-inflammatory IL-1β (p = 0.097), G-CSF, (p = 0.067) and KC (p = 0.05) due to TMM001-treatment was also observed (Fig 7).


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)

Treatment with TMM001 reduces the pro-inflammatory cytokine and chemokine response to B. mallei challenge.Serum cytokine/chemokine profile of PBS- or TMM001-treated mice following exposure to B. mallei CSM001 (1.5x105 CFU) at 0 h (A) and 48 h (B) post challenge. Mean ± SEM plotted are representative of three animals. Statistical significance was determined by one-way ANOVA followed by the Dunnett's test. ★ p ≤ 0.05.
© Copyright Policy
Related In: Results  -  Collection

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

pntd.0003863.g007: Treatment with TMM001 reduces the pro-inflammatory cytokine and chemokine response to B. mallei challenge.Serum cytokine/chemokine profile of PBS- or TMM001-treated mice following exposure to B. mallei CSM001 (1.5x105 CFU) at 0 h (A) and 48 h (B) post challenge. Mean ± SEM plotted are representative of three animals. Statistical significance was determined by one-way ANOVA followed by the Dunnett's test. ★ p ≤ 0.05.
Mentions: Sera that was collected at 48 h post challenge from PBS- and TMM001-treated mice was used to identify pro-inflammatory cytokine and chemokine responses that correspond with disease outcome. Prior to challenge, a similar baseline expression of cytokines and chemokines was detectable in serum of representative animals from both the PBS- and TMM001-immunized animals (Fig 7A). Following CSM001 challenge, the overall cytokine/chemokine expression increased markedly in both PBS- and TMM001-immunized animals (Fig 7B) compared to baseline, consistent with our previous observations of innate immune responses to Burkholderia species [27]. An attenuation of the pro-inflammatory serum cytokine/chemokine response to challenge was observed in the TMM001-treated compared to PBS control. The reduction of several pro-inflammatory mediators due to TMM001-treatment was significant, including IL-6 (p = 0.049), GM-CSF (p = 0.037), MCP-1 (p = 0.022), and RANTES (p = 0.032) (Fig 7). A trend for reduction of several other pro-inflammatory IL-1β (p = 0.097), G-CSF, (p = 0.067) and KC (p = 0.05) due to TMM001-treatment was also observed (Fig 7).

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