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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

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.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