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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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Pro-inflammatory factors associated with TB progression are expressed by lung phagocytic cells.F2 mice were challenged with Mtb. On day 24 post-infection, suspensions of lung cells isolated from moderately wasting mice were separated into plastic-adherent and non-adherent populations, and gene expression was analyzed by real-time PCR. A, Flow cytometry analysis of plastic-adherent and plastic-non-adherent populations. Cells were stained with mAbs specific to F4-80 and Gr-1 (clone RB6-8C5) antigens. Note enrichment for F4/80+ and Gr-1+ cells in plastic-adherent over non-adherent population (60% over 14%). B, Gene expression in plastic-adherent versus plastic-nonadherent populations (fold change in expression). Closed bars: pro-inflammatory factors associated with TB progression; open bars: factors that did not correlate with TB progression (Figure 3, Table 2 and data not shown). C, Production of TNF-α, CXCL2, IL-6, and IL-11 by different populations of lung cells (intracellular staining, two independent experiments). Cells were stained with mAbs specific to CD4, CD8, F4-80, and Ly-6G (clone 1A8) antigens. Gates are placed based on the fluorescence-minus-one control for each of analyzed subset.
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pone-0010469-g005: Pro-inflammatory factors associated with TB progression are expressed by lung phagocytic cells.F2 mice were challenged with Mtb. On day 24 post-infection, suspensions of lung cells isolated from moderately wasting mice were separated into plastic-adherent and non-adherent populations, and gene expression was analyzed by real-time PCR. A, Flow cytometry analysis of plastic-adherent and plastic-non-adherent populations. Cells were stained with mAbs specific to F4-80 and Gr-1 (clone RB6-8C5) antigens. Note enrichment for F4/80+ and Gr-1+ cells in plastic-adherent over non-adherent population (60% over 14%). B, Gene expression in plastic-adherent versus plastic-nonadherent populations (fold change in expression). Closed bars: pro-inflammatory factors associated with TB progression; open bars: factors that did not correlate with TB progression (Figure 3, Table 2 and data not shown). C, Production of TNF-α, CXCL2, IL-6, and IL-11 by different populations of lung cells (intracellular staining, two independent experiments). Cells were stained with mAbs specific to CD4, CD8, F4-80, and Ly-6G (clone 1A8) antigens. Gates are placed based on the fluorescence-minus-one control for each of analyzed subset.

Mentions: To identify cells responsible for the expression of pro-inflammatory factors in the infected lungs, we used two experimental approaches. First, we separated lung cells derived from Mtb-infected F2 mice into plastic-adherent and plastic-non-adherent populations, and compared gene expression in these populations of cells. The cells were obtained from the lungs of F2 mice, 24 days following the challenge with Mtb. Flow cytometry analysis showed that plastic adherent population was enriched for F4-80+Gr-1− (macrophages) and F4-80−Gr-1+ (presumably, granulocytes) cells that together formed more than 50% of the adherent cells (Figure 5A). In the plastic-non-adherent population, the proportion of phagocytes was significantly reduced (less than 15%, Figure 5A). In the adherent population, the expression of IL-1β, IL-6, TNF-α, CCL3, CCL4, CXCL2, as well as that of iNOS, was 8 to 30-fold higher relative to the non-adherent cells (Figure 5B), indicating lung phagocytes as the likely source of the analyzed factors.


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)

Pro-inflammatory factors associated with TB progression are expressed by lung phagocytic cells.F2 mice were challenged with Mtb. On day 24 post-infection, suspensions of lung cells isolated from moderately wasting mice were separated into plastic-adherent and non-adherent populations, and gene expression was analyzed by real-time PCR. A, Flow cytometry analysis of plastic-adherent and plastic-non-adherent populations. Cells were stained with mAbs specific to F4-80 and Gr-1 (clone RB6-8C5) antigens. Note enrichment for F4/80+ and Gr-1+ cells in plastic-adherent over non-adherent population (60% over 14%). B, Gene expression in plastic-adherent versus plastic-nonadherent populations (fold change in expression). Closed bars: pro-inflammatory factors associated with TB progression; open bars: factors that did not correlate with TB progression (Figure 3, Table 2 and data not shown). C, Production of TNF-α, CXCL2, IL-6, and IL-11 by different populations of lung cells (intracellular staining, two independent experiments). Cells were stained with mAbs specific to CD4, CD8, F4-80, and Ly-6G (clone 1A8) antigens. Gates are placed based on the fluorescence-minus-one control for each of analyzed subset.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC2864263&req=5

pone-0010469-g005: Pro-inflammatory factors associated with TB progression are expressed by lung phagocytic cells.F2 mice were challenged with Mtb. On day 24 post-infection, suspensions of lung cells isolated from moderately wasting mice were separated into plastic-adherent and non-adherent populations, and gene expression was analyzed by real-time PCR. A, Flow cytometry analysis of plastic-adherent and plastic-non-adherent populations. Cells were stained with mAbs specific to F4-80 and Gr-1 (clone RB6-8C5) antigens. Note enrichment for F4/80+ and Gr-1+ cells in plastic-adherent over non-adherent population (60% over 14%). B, Gene expression in plastic-adherent versus plastic-nonadherent populations (fold change in expression). Closed bars: pro-inflammatory factors associated with TB progression; open bars: factors that did not correlate with TB progression (Figure 3, Table 2 and data not shown). C, Production of TNF-α, CXCL2, IL-6, and IL-11 by different populations of lung cells (intracellular staining, two independent experiments). Cells were stained with mAbs specific to CD4, CD8, F4-80, and Ly-6G (clone 1A8) antigens. Gates are placed based on the fluorescence-minus-one control for each of analyzed subset.
Mentions: To identify cells responsible for the expression of pro-inflammatory factors in the infected lungs, we used two experimental approaches. First, we separated lung cells derived from Mtb-infected F2 mice into plastic-adherent and plastic-non-adherent populations, and compared gene expression in these populations of cells. The cells were obtained from the lungs of F2 mice, 24 days following the challenge with Mtb. Flow cytometry analysis showed that plastic adherent population was enriched for F4-80+Gr-1− (macrophages) and F4-80−Gr-1+ (presumably, granulocytes) cells that together formed more than 50% of the adherent cells (Figure 5A). In the plastic-non-adherent population, the proportion of phagocytes was significantly reduced (less than 15%, Figure 5A). In the adherent population, the expression of IL-1β, IL-6, TNF-α, CCL3, CCL4, CXCL2, as well as that of iNOS, was 8 to 30-fold higher relative to the non-adherent cells (Figure 5B), indicating lung phagocytes as the likely source of the analyzed factors.

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