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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

Fibrosis in the lungs of vaccinated and uninfected or Mtb-infected mice. ((a)-(b)) Masson's trichrome stained lung section of BCG vaccinated (for 8 weeks) and uninfected (a) or Mtb-infected (b) mice. ((c)-(d)) Masson's trichrome stained lung section of ΔbfrB vaccinated (for 8 weeks) and uninfected (c) or Mtb-infected (d) mice. The arrows in (a) and (c) show basal level of fibrosis (blue color). The arrows in (b) show minimal fibrosis in the BCG vaccinated and Mtb-infected mice. The arrows in (d) show extensive fibrosis in the ΔbfrB vaccinated and Mtb-infected mice. Magnification: 4x ((a) and (c)) or 40x ((b) and (d)). (e) Intensity plot of significantly differentially expressed genes involved in the fibrosis network. The values plotted are the difference in fold change 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 +2 (red) to −2 (blue).
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fig5: Fibrosis in the lungs of vaccinated and uninfected or Mtb-infected mice. ((a)-(b)) Masson's trichrome stained lung section of BCG vaccinated (for 8 weeks) and uninfected (a) or Mtb-infected (b) mice. ((c)-(d)) Masson's trichrome stained lung section of ΔbfrB vaccinated (for 8 weeks) and uninfected (c) or Mtb-infected (d) mice. The arrows in (a) and (c) show basal level of fibrosis (blue color). The arrows in (b) show minimal fibrosis in the BCG vaccinated and Mtb-infected mice. The arrows in (d) show extensive fibrosis in the ΔbfrB vaccinated and Mtb-infected mice. Magnification: 4x ((a) and (c)) or 40x ((b) and (d)). (e) Intensity plot of significantly differentially expressed genes involved in the fibrosis network. The values plotted are the difference in fold change 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 +2 (red) to −2 (blue).

Mentions: The lungs of ΔbfrB or BCG vaccinated, uninfected mice had similar levels of background fibrosis (Figures 5(a) and 5(c)). Among the Mtb-infected mice, those vaccinated with ΔbfrB had more abundant fibrosis than the BCG vaccinated animals (Figures 5(b) and 5(d)). These collagen fibers were predominantly present at the periphery of the granulomas and appeared in distinct clusters in the ΔbfrB vaccinated mice, compared to a more diffused pattern seen in the BCG vaccinated mice. We also interrogated the SDEG to determine the expression pattern of genes associated with fibrosis in these vaccinated and Mtb-infected mice lungs. The IPA analysis of SDEG identified a subset of 39 genes enriched for fibrosis and tissue remodeling network (Figure 5(e) and Supplementary Table  3). Of these, 27 were upregulated and 12 were downregulated in the ΔbfrB vaccinated, relative to the BCG vaccinated, Mtb-infected mice lungs. The expression pattern of genes predicted activation of fibrosis network in the ΔbfrB vaccinated Mtb-infected mice. In fact, the products of several of the upregulated genes, including Col4a5, Col14a1, and Timp2, are reported to be directly involved in the regulation of collagen synthesis/metabolism [12–14].


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

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

Fibrosis in the lungs of vaccinated and uninfected or Mtb-infected mice. ((a)-(b)) Masson's trichrome stained lung section of BCG vaccinated (for 8 weeks) and uninfected (a) or Mtb-infected (b) mice. ((c)-(d)) Masson's trichrome stained lung section of ΔbfrB vaccinated (for 8 weeks) and uninfected (c) or Mtb-infected (d) mice. The arrows in (a) and (c) show basal level of fibrosis (blue color). The arrows in (b) show minimal fibrosis in the BCG vaccinated and Mtb-infected mice. The arrows in (d) show extensive fibrosis in the ΔbfrB vaccinated and Mtb-infected mice. Magnification: 4x ((a) and (c)) or 40x ((b) and (d)). (e) Intensity plot of significantly differentially expressed genes involved in the fibrosis network. The values plotted are the difference in fold change 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 +2 (red) to −2 (blue).
© Copyright Policy - open-access
Related In: Results  -  Collection

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fig5: Fibrosis in the lungs of vaccinated and uninfected or Mtb-infected mice. ((a)-(b)) Masson's trichrome stained lung section of BCG vaccinated (for 8 weeks) and uninfected (a) or Mtb-infected (b) mice. ((c)-(d)) Masson's trichrome stained lung section of ΔbfrB vaccinated (for 8 weeks) and uninfected (c) or Mtb-infected (d) mice. The arrows in (a) and (c) show basal level of fibrosis (blue color). The arrows in (b) show minimal fibrosis in the BCG vaccinated and Mtb-infected mice. The arrows in (d) show extensive fibrosis in the ΔbfrB vaccinated and Mtb-infected mice. Magnification: 4x ((a) and (c)) or 40x ((b) and (d)). (e) Intensity plot of significantly differentially expressed genes involved in the fibrosis network. The values plotted are the difference in fold change 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 +2 (red) to −2 (blue).
Mentions: The lungs of ΔbfrB or BCG vaccinated, uninfected mice had similar levels of background fibrosis (Figures 5(a) and 5(c)). Among the Mtb-infected mice, those vaccinated with ΔbfrB had more abundant fibrosis than the BCG vaccinated animals (Figures 5(b) and 5(d)). These collagen fibers were predominantly present at the periphery of the granulomas and appeared in distinct clusters in the ΔbfrB vaccinated mice, compared to a more diffused pattern seen in the BCG vaccinated mice. We also interrogated the SDEG to determine the expression pattern of genes associated with fibrosis in these vaccinated and Mtb-infected mice lungs. The IPA analysis of SDEG identified a subset of 39 genes enriched for fibrosis and tissue remodeling network (Figure 5(e) and Supplementary Table  3). Of these, 27 were upregulated and 12 were downregulated in the ΔbfrB vaccinated, relative to the BCG vaccinated, Mtb-infected mice lungs. The expression pattern of genes predicted activation of fibrosis network in the ΔbfrB vaccinated Mtb-infected mice. In fact, the products of several of the upregulated genes, including Col4a5, Col14a1, and Timp2, are reported to be directly involved in the regulation of collagen synthesis/metabolism [12–14].

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