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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

Histopathology of vaccinated and uninfected or Mtb-infected mice lungs. ((a)-(b)) H&E stained lung section of BCG vaccinated (for 8 weeks) and uninfected mice. ((c)-(d)) H&E stained lung section of ΔbfrB vaccinated (for 8 weeks) and uninfected mice. The arrow in (c) shows cellular aggregation. The arrows in (d) show foamy histiocytes. ((e)-(f)) H&E stained lung section of BCG vaccinated (for 8 weeks) and Mtb-infected (for 4 weeks) mice. The arrows in (e) show a multifocal, coalescent granuloma. The arrows in (f) show lymphocyte cuff at the periphery of a granuloma. ((g)-(h)) H&E stained lung section of ΔbfrB vaccinated (for 8 weeks) and Mtb-infected (for 4 weeks) mice. The arrows in (g) show multiple, smaller granulomas (compared to (e)). The arrows in (h) show lymphocyte cuff at the periphery of a granuloma. Magnification: 4x ((a), (c), (e), and (g)) or 40x ((b), (d), (f), and (h)).
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fig2: Histopathology of vaccinated and uninfected or Mtb-infected mice lungs. ((a)-(b)) H&E stained lung section of BCG vaccinated (for 8 weeks) and uninfected mice. ((c)-(d)) H&E stained lung section of ΔbfrB vaccinated (for 8 weeks) and uninfected mice. The arrow in (c) shows cellular aggregation. The arrows in (d) show foamy histiocytes. ((e)-(f)) H&E stained lung section of BCG vaccinated (for 8 weeks) and Mtb-infected (for 4 weeks) mice. The arrows in (e) show a multifocal, coalescent granuloma. The arrows in (f) show lymphocyte cuff at the periphery of a granuloma. ((g)-(h)) H&E stained lung section of ΔbfrB vaccinated (for 8 weeks) and Mtb-infected (for 4 weeks) mice. The arrows in (g) show multiple, smaller granulomas (compared to (e)). The arrows in (h) show lymphocyte cuff at the periphery of a granuloma. Magnification: 4x ((a), (c), (e), and (g)) or 40x ((b), (d), (f), and (h)).

Mentions: Analysis of the lung sections at higher magnifications revealed a mostly clear and functional parenchyma without inflammation or pneumonia in the ΔbfrB or BCG vaccinated, uninfected animals, though very few, small, localized perivascular cellular aggregates were found in the former group (Figures 2(a)–2(d)). These cellular aggregates were comprised of foamy histiocytes and lymphocytes (Figures 2(c) and 2(d)). This indicates that a distinct lung-immune response and cell recruitment was elicited by the two vaccines. Among the Mtb-infected mice, the lungs of BCG vaccinated animals had well-organized peribronchial and perivascular granulomas that occasionally coalesce to form bigger lesions (Figure 2(e)). These highly cellular and diffused granulomas contained densely arranged foamy and nonfoamy histiocytes that appear to be macrophages and polymorphonuclear cells (PMN) at the center, surrounded by a cuff of lymphocytes at the periphery (Figure 2(f)). In contrast, the granulomatous lesions in the ΔbfrB vaccinated, Mtb-infected mice lungs appeared smaller, diffused, and contained more lymphocytes at the periphery of the lesions (Figures 2(g) and 2(h)). Relatively more fibrosis was also noted in these well-confined granulomas (see below). Although no necrosis was found in any of these granulomas, elevated immune cell accumulation, specifically foamy macrophages, reminiscent of lipid-pneumonia was noted in both ΔbfrB or BCG vaccinated, Mtb-infected mice lungs (Figures 2(e)–2(h)). Morphometric analysis of lung granulomas in the Mtb-infected mice revealed about two-fold higher lesion volume, corresponding to more lung involvement, in the BCG vaccinated, compared to the ΔbfrB vaccinated animals; however, the difference was not statistically significant (Supplementary Figure  3).


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

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

Histopathology of vaccinated and uninfected or Mtb-infected mice lungs. ((a)-(b)) H&E stained lung section of BCG vaccinated (for 8 weeks) and uninfected mice. ((c)-(d)) H&E stained lung section of ΔbfrB vaccinated (for 8 weeks) and uninfected mice. The arrow in (c) shows cellular aggregation. The arrows in (d) show foamy histiocytes. ((e)-(f)) H&E stained lung section of BCG vaccinated (for 8 weeks) and Mtb-infected (for 4 weeks) mice. The arrows in (e) show a multifocal, coalescent granuloma. The arrows in (f) show lymphocyte cuff at the periphery of a granuloma. ((g)-(h)) H&E stained lung section of ΔbfrB vaccinated (for 8 weeks) and Mtb-infected (for 4 weeks) mice. The arrows in (g) show multiple, smaller granulomas (compared to (e)). The arrows in (h) show lymphocyte cuff at the periphery of a granuloma. Magnification: 4x ((a), (c), (e), and (g)) or 40x ((b), (d), (f), and (h)).
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Related In: Results  -  Collection

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fig2: Histopathology of vaccinated and uninfected or Mtb-infected mice lungs. ((a)-(b)) H&E stained lung section of BCG vaccinated (for 8 weeks) and uninfected mice. ((c)-(d)) H&E stained lung section of ΔbfrB vaccinated (for 8 weeks) and uninfected mice. The arrow in (c) shows cellular aggregation. The arrows in (d) show foamy histiocytes. ((e)-(f)) H&E stained lung section of BCG vaccinated (for 8 weeks) and Mtb-infected (for 4 weeks) mice. The arrows in (e) show a multifocal, coalescent granuloma. The arrows in (f) show lymphocyte cuff at the periphery of a granuloma. ((g)-(h)) H&E stained lung section of ΔbfrB vaccinated (for 8 weeks) and Mtb-infected (for 4 weeks) mice. The arrows in (g) show multiple, smaller granulomas (compared to (e)). The arrows in (h) show lymphocyte cuff at the periphery of a granuloma. Magnification: 4x ((a), (c), (e), and (g)) or 40x ((b), (d), (f), and (h)).
Mentions: Analysis of the lung sections at higher magnifications revealed a mostly clear and functional parenchyma without inflammation or pneumonia in the ΔbfrB or BCG vaccinated, uninfected animals, though very few, small, localized perivascular cellular aggregates were found in the former group (Figures 2(a)–2(d)). These cellular aggregates were comprised of foamy histiocytes and lymphocytes (Figures 2(c) and 2(d)). This indicates that a distinct lung-immune response and cell recruitment was elicited by the two vaccines. Among the Mtb-infected mice, the lungs of BCG vaccinated animals had well-organized peribronchial and perivascular granulomas that occasionally coalesce to form bigger lesions (Figure 2(e)). These highly cellular and diffused granulomas contained densely arranged foamy and nonfoamy histiocytes that appear to be macrophages and polymorphonuclear cells (PMN) at the center, surrounded by a cuff of lymphocytes at the periphery (Figure 2(f)). In contrast, the granulomatous lesions in the ΔbfrB vaccinated, Mtb-infected mice lungs appeared smaller, diffused, and contained more lymphocytes at the periphery of the lesions (Figures 2(g) and 2(h)). Relatively more fibrosis was also noted in these well-confined granulomas (see below). Although no necrosis was found in any of these granulomas, elevated immune cell accumulation, specifically foamy macrophages, reminiscent of lipid-pneumonia was noted in both ΔbfrB or BCG vaccinated, Mtb-infected mice lungs (Figures 2(e)–2(h)). Morphometric analysis of lung granulomas in the Mtb-infected mice revealed about two-fold higher lesion volume, corresponding to more lung involvement, in the BCG vaccinated, compared to the ΔbfrB vaccinated animals; however, the difference was not statistically significant (Supplementary Figure  3).

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