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In mice, tuberculosis progression is associated with intensive inflammatory response and the accumulation of Gr-1 cells in the lungs.

Lyadova IV, Tsiganov EN, Kapina MA, Shepelkova GS, Sosunov VV, Radaeva TV, Majorov KB, Shmitova NS, van den Ham HJ, Ganusov VV, De Boer RJ, Racine R, Winslow GM - PLoS ONE (2010)

Bottom Line: Infection with Mycobacterium tuberculosis (Mtb) results in different clinical outcomes ranging from asymptomatic containment to rapidly progressing tuberculosis (TB).TNF-alpha had both protective and harmful effects.Local accumulation of Gr-1(dim) cells is a newly identified feature of progressing TB.

View Article: PubMed Central - PubMed

Affiliation: Department of Immunology, Central Tuberculosis Research Institute, Russian Academy of Medical Sciences, Moscow, Russian Federation. ivlyadova@mail.ru

ABSTRACT

Background: Infection with Mycobacterium tuberculosis (Mtb) results in different clinical outcomes ranging from asymptomatic containment to rapidly progressing tuberculosis (TB). The mechanisms controlling TB progression in immunologically-competent hosts remain unclear.

Methodology/principal findings: To address these mechanisms, we analyzed TB progression in a panel of genetically heterogeneous (A/SnxI/St) F2 mice, originating from TB-highly-susceptible I/St and more resistant A/Sn mice. In F2 mice the rates of TB progression differed. In mice that did not reach terminal stage of infection, TB progression did not correlate with lung Mtb loads. Nor was TB progression correlated with lung expression of factors involved in antibacterial immunity, such as iNOS, IFN-gamma, or IL-12p40. The major characteristics of progressing TB was high lung expression of the inflammation-related factors IL-1beta, IL-6, IL-11 (p<0.0003); CCL3, CCL4, CXCL2 (p<0.002); MMP-8 (p<0.0001). The major predictors of TB progression were high expressions of IL-1beta and IL-11. TNF-alpha had both protective and harmful effects. Factors associated with TB progression were expressed mainly by macrophages (F4-80(+) cells) and granulocytes (Gr-1(hi)/Ly-6G(hi) cells). Macrophages and granulocytes from I/St and A/Sn parental strains exhibited intrinsic differences in the expression of inflammatory factors, suggesting that genetically determined peculiarities of phagocytes transcriptional response could account for the peculiarities of gene expression in the infected lungs. Another characteristic feature of progressing TB was the accumulation in the infected lungs of Gr-1(dim) cells that could contribute to TB progression.

Conclusions/significance: In a population of immunocompetent hosts, the outcome of TB depends on quantitatively- and genetically-controlled differences in the intensity of inflammatory responses, rather than being a direct consequence of mycobacterial colonization. Local accumulation of Gr-1(dim) cells is a newly identified feature of progressing TB. High expression of IL-1beta and IL-11 are potential risk factors for TB progression and possible targets for TB immunomodulation.

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TB-susceptible I/St and TB-resistant A/Sn mice infected with Mtb differ by the expression of genes associated with T-cell mediated response and inflammation.I/St and A/Sn mice were challenged with Mtb or left un-infected. The expression of genes was analyzed in the lungs at weeks 0, 1, 3, and 5 post-challenge. Shown are typical examples of the expression of genes which were down-regulated in I/St lungs at late time-points post-challenge (IFN-γ, IL-12p40), up-regulated in I/St lungs at late time-points post-challenge (IL-1β, iNOS), up-regulated in I/St lungs at all time-points post-infection (MMP-8), and genes that were expressed similarly in I/St and A/Sn lungs (IL-10). Mean ±SD are shown (n = 3–4 per time-point). I/St, dashed line; A/Sn, solid line.
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pone-0010469-g002: TB-susceptible I/St and TB-resistant A/Sn mice infected with Mtb differ by the expression of genes associated with T-cell mediated response and inflammation.I/St and A/Sn mice were challenged with Mtb or left un-infected. The expression of genes was analyzed in the lungs at weeks 0, 1, 3, and 5 post-challenge. Shown are typical examples of the expression of genes which were down-regulated in I/St lungs at late time-points post-challenge (IFN-γ, IL-12p40), up-regulated in I/St lungs at late time-points post-challenge (IL-1β, iNOS), up-regulated in I/St lungs at all time-points post-infection (MMP-8), and genes that were expressed similarly in I/St and A/Sn lungs (IL-10). Mean ±SD are shown (n = 3–4 per time-point). I/St, dashed line; A/Sn, solid line.

Mentions: The first set of experiments was performed in I/St and A/Sn mice, and addressed the expression of factors involved in the antibacterial immune response (i.e., IFN-γ, TNF-α, IL-10, IL-12p40, T-bet, iNOS), inflammation (IL-1β, IL-6, TNF-α, CCL2, CCL5, CXCL2, iNOS), and factors that previously had been shown to be differentially expressed in I/St and A/Sn mice (IL-6, IL-11, MMP-8, MMP-10 [18], [20]). Mice were challenged with Mtb, and gene expression in the lung tissue was analyzed using quantitative PCR at weeks 0, 1, 3, and 5 post-challenge. Until the third week post-infection, the expression of the majority of genes analyzed were similar in mice of both strains. By week five, the expression of genes associated with T cell-mediated antibacterial immune response (IL-12p40, IFN-γ, T-bet, CCL5) declined in I/St mice, resulting in a relative deficiency of these factors in the lungs of susceptible mice (Figure 2 and data not shown). In contrast, the expression of inflammation-related genes (IL-1β, IL-6, TNF-α, CXCL2) and iNOS increased in I/St lungs, resulting in a relative abundance of these factors in the lungs of susceptible mice. The expression of IL-10 and CCL2 did not differ significantly between the mice at any time-point. In contrast, IL-11, MMP-8, and MMP-10 were over expressed in I/St mice at all analyzed time-points (Figure 2 and data not shown).


In mice, tuberculosis progression is associated with intensive inflammatory response and the accumulation of Gr-1 cells in the lungs.

Lyadova IV, Tsiganov EN, Kapina MA, Shepelkova GS, Sosunov VV, Radaeva TV, Majorov KB, Shmitova NS, van den Ham HJ, Ganusov VV, De Boer RJ, Racine R, Winslow GM - PLoS ONE (2010)

TB-susceptible I/St and TB-resistant A/Sn mice infected with Mtb differ by the expression of genes associated with T-cell mediated response and inflammation.I/St and A/Sn mice were challenged with Mtb or left un-infected. The expression of genes was analyzed in the lungs at weeks 0, 1, 3, and 5 post-challenge. Shown are typical examples of the expression of genes which were down-regulated in I/St lungs at late time-points post-challenge (IFN-γ, IL-12p40), up-regulated in I/St lungs at late time-points post-challenge (IL-1β, iNOS), up-regulated in I/St lungs at all time-points post-infection (MMP-8), and genes that were expressed similarly in I/St and A/Sn lungs (IL-10). Mean ±SD are shown (n = 3–4 per time-point). I/St, dashed line; A/Sn, solid line.
© Copyright Policy
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC2864263&req=5

pone-0010469-g002: TB-susceptible I/St and TB-resistant A/Sn mice infected with Mtb differ by the expression of genes associated with T-cell mediated response and inflammation.I/St and A/Sn mice were challenged with Mtb or left un-infected. The expression of genes was analyzed in the lungs at weeks 0, 1, 3, and 5 post-challenge. Shown are typical examples of the expression of genes which were down-regulated in I/St lungs at late time-points post-challenge (IFN-γ, IL-12p40), up-regulated in I/St lungs at late time-points post-challenge (IL-1β, iNOS), up-regulated in I/St lungs at all time-points post-infection (MMP-8), and genes that were expressed similarly in I/St and A/Sn lungs (IL-10). Mean ±SD are shown (n = 3–4 per time-point). I/St, dashed line; A/Sn, solid line.
Mentions: The first set of experiments was performed in I/St and A/Sn mice, and addressed the expression of factors involved in the antibacterial immune response (i.e., IFN-γ, TNF-α, IL-10, IL-12p40, T-bet, iNOS), inflammation (IL-1β, IL-6, TNF-α, CCL2, CCL5, CXCL2, iNOS), and factors that previously had been shown to be differentially expressed in I/St and A/Sn mice (IL-6, IL-11, MMP-8, MMP-10 [18], [20]). Mice were challenged with Mtb, and gene expression in the lung tissue was analyzed using quantitative PCR at weeks 0, 1, 3, and 5 post-challenge. Until the third week post-infection, the expression of the majority of genes analyzed were similar in mice of both strains. By week five, the expression of genes associated with T cell-mediated antibacterial immune response (IL-12p40, IFN-γ, T-bet, CCL5) declined in I/St mice, resulting in a relative deficiency of these factors in the lungs of susceptible mice (Figure 2 and data not shown). In contrast, the expression of inflammation-related genes (IL-1β, IL-6, TNF-α, CXCL2) and iNOS increased in I/St lungs, resulting in a relative abundance of these factors in the lungs of susceptible mice. The expression of IL-10 and CCL2 did not differ significantly between the mice at any time-point. In contrast, IL-11, MMP-8, and MMP-10 were over expressed in I/St mice at all analyzed time-points (Figure 2 and data not shown).

Bottom Line: Infection with Mycobacterium tuberculosis (Mtb) results in different clinical outcomes ranging from asymptomatic containment to rapidly progressing tuberculosis (TB).TNF-alpha had both protective and harmful effects.Local accumulation of Gr-1(dim) cells is a newly identified feature of progressing TB.

View Article: PubMed Central - PubMed

Affiliation: Department of Immunology, Central Tuberculosis Research Institute, Russian Academy of Medical Sciences, Moscow, Russian Federation. ivlyadova@mail.ru

ABSTRACT

Background: Infection with Mycobacterium tuberculosis (Mtb) results in different clinical outcomes ranging from asymptomatic containment to rapidly progressing tuberculosis (TB). The mechanisms controlling TB progression in immunologically-competent hosts remain unclear.

Methodology/principal findings: To address these mechanisms, we analyzed TB progression in a panel of genetically heterogeneous (A/SnxI/St) F2 mice, originating from TB-highly-susceptible I/St and more resistant A/Sn mice. In F2 mice the rates of TB progression differed. In mice that did not reach terminal stage of infection, TB progression did not correlate with lung Mtb loads. Nor was TB progression correlated with lung expression of factors involved in antibacterial immunity, such as iNOS, IFN-gamma, or IL-12p40. The major characteristics of progressing TB was high lung expression of the inflammation-related factors IL-1beta, IL-6, IL-11 (p<0.0003); CCL3, CCL4, CXCL2 (p<0.002); MMP-8 (p<0.0001). The major predictors of TB progression were high expressions of IL-1beta and IL-11. TNF-alpha had both protective and harmful effects. Factors associated with TB progression were expressed mainly by macrophages (F4-80(+) cells) and granulocytes (Gr-1(hi)/Ly-6G(hi) cells). Macrophages and granulocytes from I/St and A/Sn parental strains exhibited intrinsic differences in the expression of inflammatory factors, suggesting that genetically determined peculiarities of phagocytes transcriptional response could account for the peculiarities of gene expression in the infected lungs. Another characteristic feature of progressing TB was the accumulation in the infected lungs of Gr-1(dim) cells that could contribute to TB progression.

Conclusions/significance: In a population of immunocompetent hosts, the outcome of TB depends on quantitatively- and genetically-controlled differences in the intensity of inflammatory responses, rather than being a direct consequence of mycobacterial colonization. Local accumulation of Gr-1(dim) cells is a newly identified feature of progressing TB. High expression of IL-1beta and IL-11 are potential risk factors for TB progression and possible targets for TB immunomodulation.

Show MeSH
Related in: MedlinePlus