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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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F2 mice display different rates of TB progression.F2 mice were challenged i.t. with 103 CFU of Mtb. Weight was monitored once a week. A, Kinetics of weight change. 100% - weight on day 1 post-infection. Shown are representative results obtained in two (n = 52) independent experiments that included mice of both sexes. B–D, Mycobacterial load (B), lung pathology (C), and lung cell viability (D) in mice displaying different degree of wasting. Severely wasting mice (wasting by more than 20%) are indicated by blue circles. Lines show the predictions of the linear regression when all mice are included in the analysis (dashed blue lines) or when severely wasting mice are excluded from the analysis (solid black lines). ρ, Spearman correlation coefficient; p, p-value for ANOVA. E, F, Examples of lung tissue sections and lung cell flow cytometry representing two extremes with mild and severe pathology. Numbers in F indicate the percentages of dead (left) and live (right) cells. G, H, Long-term monitoring of F2 mice (n = 30, two independent experiments). G, The kinetics of weight change. H, Comparison of mycobacterial loads observed on days 24 and 140 post-infection.
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pone-0010469-g001: F2 mice display different rates of TB progression.F2 mice were challenged i.t. with 103 CFU of Mtb. Weight was monitored once a week. A, Kinetics of weight change. 100% - weight on day 1 post-infection. Shown are representative results obtained in two (n = 52) independent experiments that included mice of both sexes. B–D, Mycobacterial load (B), lung pathology (C), and lung cell viability (D) in mice displaying different degree of wasting. Severely wasting mice (wasting by more than 20%) are indicated by blue circles. Lines show the predictions of the linear regression when all mice are included in the analysis (dashed blue lines) or when severely wasting mice are excluded from the analysis (solid black lines). ρ, Spearman correlation coefficient; p, p-value for ANOVA. E, F, Examples of lung tissue sections and lung cell flow cytometry representing two extremes with mild and severe pathology. Numbers in F indicate the percentages of dead (left) and live (right) cells. G, H, Long-term monitoring of F2 mice (n = 30, two independent experiments). G, The kinetics of weight change. H, Comparison of mycobacterial loads observed on days 24 and 140 post-infection.

Mentions: In the first set of experiments we analyzed the kinetics of TB progression and addressed the correlation between TB progression, mycobacterial multiplication, and lung tissue pathology in (A/SnxI/St) F2 mice. F2 mice originated from TB-highly-susceptible I/St and more resistant A/Sn mice. The mice were infected with Mtb, and TB progression was monitored by evaluating post-infection body weight loss, a vital indicator of TB severity in experimental animals and humans (Figure 1). During the first 2 weeks of infection, all mice gained weight. At the end of week 3, some mice started to undergo wasting. On day 24, the mice displayed a great variability in the degree of wasting (Figure 1A). At this time, lungs were isolated from individual mice and used for: (i) determination of mycobacterial load, (ii) examination of lung tissue pathology, (iii) flow cytometry analysis, and (iv) gene expression analysis.


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)

F2 mice display different rates of TB progression.F2 mice were challenged i.t. with 103 CFU of Mtb. Weight was monitored once a week. A, Kinetics of weight change. 100% - weight on day 1 post-infection. Shown are representative results obtained in two (n = 52) independent experiments that included mice of both sexes. B–D, Mycobacterial load (B), lung pathology (C), and lung cell viability (D) in mice displaying different degree of wasting. Severely wasting mice (wasting by more than 20%) are indicated by blue circles. Lines show the predictions of the linear regression when all mice are included in the analysis (dashed blue lines) or when severely wasting mice are excluded from the analysis (solid black lines). ρ, Spearman correlation coefficient; p, p-value for ANOVA. E, F, Examples of lung tissue sections and lung cell flow cytometry representing two extremes with mild and severe pathology. Numbers in F indicate the percentages of dead (left) and live (right) cells. G, H, Long-term monitoring of F2 mice (n = 30, two independent experiments). G, The kinetics of weight change. H, Comparison of mycobacterial loads observed on days 24 and 140 post-infection.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC2864263&req=5

pone-0010469-g001: F2 mice display different rates of TB progression.F2 mice were challenged i.t. with 103 CFU of Mtb. Weight was monitored once a week. A, Kinetics of weight change. 100% - weight on day 1 post-infection. Shown are representative results obtained in two (n = 52) independent experiments that included mice of both sexes. B–D, Mycobacterial load (B), lung pathology (C), and lung cell viability (D) in mice displaying different degree of wasting. Severely wasting mice (wasting by more than 20%) are indicated by blue circles. Lines show the predictions of the linear regression when all mice are included in the analysis (dashed blue lines) or when severely wasting mice are excluded from the analysis (solid black lines). ρ, Spearman correlation coefficient; p, p-value for ANOVA. E, F, Examples of lung tissue sections and lung cell flow cytometry representing two extremes with mild and severe pathology. Numbers in F indicate the percentages of dead (left) and live (right) cells. G, H, Long-term monitoring of F2 mice (n = 30, two independent experiments). G, The kinetics of weight change. H, Comparison of mycobacterial loads observed on days 24 and 140 post-infection.
Mentions: In the first set of experiments we analyzed the kinetics of TB progression and addressed the correlation between TB progression, mycobacterial multiplication, and lung tissue pathology in (A/SnxI/St) F2 mice. F2 mice originated from TB-highly-susceptible I/St and more resistant A/Sn mice. The mice were infected with Mtb, and TB progression was monitored by evaluating post-infection body weight loss, a vital indicator of TB severity in experimental animals and humans (Figure 1). During the first 2 weeks of infection, all mice gained weight. At the end of week 3, some mice started to undergo wasting. On day 24, the mice displayed a great variability in the degree of wasting (Figure 1A). At this time, lungs were isolated from individual mice and used for: (i) determination of mycobacterial load, (ii) examination of lung tissue pathology, (iii) flow cytometry analysis, and (iv) gene expression analysis.

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