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Vaccination with an Attenuated Ferritin Mutant Protects Mice against Virulent Mycobacterium tuberculosis.

Subbian S, Pandey R, Soteropoulos P, Rodriguez GM - J Immunol Res (2015)

Bottom Line: The results show that the protection elicited by immunization with the bfrB mutant is comparable to BCG vaccination with respect to reduction of bacterial burden.However, significant distinctions in the disease pathology and host genome-wide lung transcriptome suggest improved containment of Mtb infection in animals vaccinated with the bfrB mutant, compared to BCG.We found that downmodulation of inflammatory response and enhanced fibrosis, compared to BCG vaccination, is associated with the protective response elicited by the bfrB mutant.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Mycobacterial Immunity and Pathogenesis, Rutgers, The State University of New Jersey, 225 Warren Street, Newark, NJ 07103, USA.

ABSTRACT
Mycobacterium tuberculosis the causative agent of tuberculosis affects millions of people worldwide. New tools for treatment and prevention of tuberculosis are urgently needed. We previously showed that a ferritin (bfrB) mutant of M. tuberculosis has altered iron homeostasis and increased sensitivity to antibiotics and to microbicidal effectors produced by activated macrophages. Most importantly, M. tuberculosis lacking BfrB is strongly attenuated in mice, especially, during the chronic phase of infection. In this study, we examined whether immunization with a bfrB mutant could confer protection against subsequent infection with virulent M. tuberculosis in a mouse model. The results show that the protection elicited by immunization with the bfrB mutant is comparable to BCG vaccination with respect to reduction of bacterial burden. However, significant distinctions in the disease pathology and host genome-wide lung transcriptome suggest improved containment of Mtb infection in animals vaccinated with the bfrB mutant, compared to BCG. We found that downmodulation of inflammatory response and enhanced fibrosis, compared to BCG vaccination, is associated with the protective response elicited by the bfrB mutant.

No MeSH data available.


Related in: MedlinePlus

Genome-wide gene expression profiling of vaccinated and Mtb-infected mice lungs. (a) Principal component analysis of lung transcriptome data from ΔbfrB (blue) or BCG (red) vaccinated, Mtb-infected mice. The eclipse around each group denotes the standard deviation of the datasets. (b) Volcano plot of lung global gene expression showing the P value significance (y-axis; log scale) and fold change (x-axis). Upregulated genes are shaded in purple and downregulated genes are in yellow. N/C denotes no change. Each spot (blue) in the plot corresponds to a gene. (c) Intensity plot and dendrogram of significantly differentially expressed genes in the ΔbfrB vaccinated, compared to BCG vaccinated, Mtb-infected mice lungs. Upregulated genes are in red and downregulated genes are in blue. The color scale bar ranges from +3 (red) to −3 (blue).
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fig3: Genome-wide gene expression profiling of vaccinated and Mtb-infected mice lungs. (a) Principal component analysis of lung transcriptome data from ΔbfrB (blue) or BCG (red) vaccinated, Mtb-infected mice. The eclipse around each group denotes the standard deviation of the datasets. (b) Volcano plot of lung global gene expression showing the P value significance (y-axis; log scale) and fold change (x-axis). Upregulated genes are shaded in purple and downregulated genes are in yellow. N/C denotes no change. Each spot (blue) in the plot corresponds to a gene. (c) Intensity plot and dendrogram of significantly differentially expressed genes in the ΔbfrB vaccinated, compared to BCG vaccinated, Mtb-infected mice lungs. Upregulated genes are in red and downregulated genes are in blue. The color scale bar ranges from +3 (red) to −3 (blue).

Mentions: The principal component analysis (PCA) mapping showed clustering of dataset from multiple samples within each group that was distinct from each other (Figure 3(a)). The reproducibility of variance in the x-axis, y-axis, and z-axis as shown by PC#1, 2, and 3 were 45.6%, 20.7%, and 14.7%, respectively. Of the 35,556 probes present in the mouse microarray, 21,760 were annotated. After normalization, data from the two vaccinated groups (ΔbfrB versus BCG) were analyzed by one-way ANOVA and compared groupwise (Figure 3(b)). Using 5% false discovery rate (FDR) (Q value < 0.05) as significance cut-off, we identified 1,545 significantly differentially expressed genes (SDEG). Of these SDEG, about 61% were upregulated in the ΔbfrB vaccinated, relative to the BCG vaccinated, Mtb-infected mouse lungs (Figures 3(b) and 3(c)). The microarray gene expression data was validated with qPCR on a randomly selected list of genes (Supplementary Table  2). The pattern and directionality of expression of selected genes was consistent between microarray and qPCR, though the absolute expression levels for some genes were different, due to inherent differences in these two methodologies.


Vaccination with an Attenuated Ferritin Mutant Protects Mice against Virulent Mycobacterium tuberculosis.

Subbian S, Pandey R, Soteropoulos P, Rodriguez GM - J Immunol Res (2015)

Genome-wide gene expression profiling of vaccinated and Mtb-infected mice lungs. (a) Principal component analysis of lung transcriptome data from ΔbfrB (blue) or BCG (red) vaccinated, Mtb-infected mice. The eclipse around each group denotes the standard deviation of the datasets. (b) Volcano plot of lung global gene expression showing the P value significance (y-axis; log scale) and fold change (x-axis). Upregulated genes are shaded in purple and downregulated genes are in yellow. N/C denotes no change. Each spot (blue) in the plot corresponds to a gene. (c) Intensity plot and dendrogram of significantly differentially expressed genes in the ΔbfrB vaccinated, compared to BCG vaccinated, Mtb-infected mice lungs. Upregulated genes are in red and downregulated genes are in blue. The color scale bar ranges from +3 (red) to −3 (blue).
© Copyright Policy - open-access
Related In: Results  -  Collection

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fig3: Genome-wide gene expression profiling of vaccinated and Mtb-infected mice lungs. (a) Principal component analysis of lung transcriptome data from ΔbfrB (blue) or BCG (red) vaccinated, Mtb-infected mice. The eclipse around each group denotes the standard deviation of the datasets. (b) Volcano plot of lung global gene expression showing the P value significance (y-axis; log scale) and fold change (x-axis). Upregulated genes are shaded in purple and downregulated genes are in yellow. N/C denotes no change. Each spot (blue) in the plot corresponds to a gene. (c) Intensity plot and dendrogram of significantly differentially expressed genes in the ΔbfrB vaccinated, compared to BCG vaccinated, Mtb-infected mice lungs. Upregulated genes are in red and downregulated genes are in blue. The color scale bar ranges from +3 (red) to −3 (blue).
Mentions: The principal component analysis (PCA) mapping showed clustering of dataset from multiple samples within each group that was distinct from each other (Figure 3(a)). The reproducibility of variance in the x-axis, y-axis, and z-axis as shown by PC#1, 2, and 3 were 45.6%, 20.7%, and 14.7%, respectively. Of the 35,556 probes present in the mouse microarray, 21,760 were annotated. After normalization, data from the two vaccinated groups (ΔbfrB versus BCG) were analyzed by one-way ANOVA and compared groupwise (Figure 3(b)). Using 5% false discovery rate (FDR) (Q value < 0.05) as significance cut-off, we identified 1,545 significantly differentially expressed genes (SDEG). Of these SDEG, about 61% were upregulated in the ΔbfrB vaccinated, relative to the BCG vaccinated, Mtb-infected mouse lungs (Figures 3(b) and 3(c)). The microarray gene expression data was validated with qPCR on a randomly selected list of genes (Supplementary Table  2). The pattern and directionality of expression of selected genes was consistent between microarray and qPCR, though the absolute expression levels for some genes were different, due to inherent differences in these two methodologies.

Bottom Line: The results show that the protection elicited by immunization with the bfrB mutant is comparable to BCG vaccination with respect to reduction of bacterial burden.However, significant distinctions in the disease pathology and host genome-wide lung transcriptome suggest improved containment of Mtb infection in animals vaccinated with the bfrB mutant, compared to BCG.We found that downmodulation of inflammatory response and enhanced fibrosis, compared to BCG vaccination, is associated with the protective response elicited by the bfrB mutant.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Mycobacterial Immunity and Pathogenesis, Rutgers, The State University of New Jersey, 225 Warren Street, Newark, NJ 07103, USA.

ABSTRACT
Mycobacterium tuberculosis the causative agent of tuberculosis affects millions of people worldwide. New tools for treatment and prevention of tuberculosis are urgently needed. We previously showed that a ferritin (bfrB) mutant of M. tuberculosis has altered iron homeostasis and increased sensitivity to antibiotics and to microbicidal effectors produced by activated macrophages. Most importantly, M. tuberculosis lacking BfrB is strongly attenuated in mice, especially, during the chronic phase of infection. In this study, we examined whether immunization with a bfrB mutant could confer protection against subsequent infection with virulent M. tuberculosis in a mouse model. The results show that the protection elicited by immunization with the bfrB mutant is comparable to BCG vaccination with respect to reduction of bacterial burden. However, significant distinctions in the disease pathology and host genome-wide lung transcriptome suggest improved containment of Mtb infection in animals vaccinated with the bfrB mutant, compared to BCG. We found that downmodulation of inflammatory response and enhanced fibrosis, compared to BCG vaccination, is associated with the protective response elicited by the bfrB mutant.

No MeSH data available.


Related in: MedlinePlus