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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 exhibiting similar mycobacterial loads display different rates of TB progression that positively correlate with the lung inflammatory response.F2 mice challenged with Mtb were divided into several groups, each having similar Mtb loads. Correlations between wasting, mycobacterial load, and cytokine/chemokine expression in mice with lung mycobacterial burdens ranging from 3.3×107 to 1×108 CFUs/lobe are shown (for Spearman correlation coefficients and p-values see Table 3).
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pone-0010469-g004: F2 mice exhibiting similar mycobacterial loads display different rates of TB progression that positively correlate with the lung inflammatory response.F2 mice challenged with Mtb were divided into several groups, each having similar Mtb loads. Correlations between wasting, mycobacterial load, and cytokine/chemokine expression in mice with lung mycobacterial burdens ranging from 3.3×107 to 1×108 CFUs/lobe are shown (for Spearman correlation coefficients and p-values see Table 3).

Mentions: There is no doubt that the host inflammatory reaction is driven by pathogen-derived signals [21], [22], and that the intensity of the inflammatory response depends on the quantity of pathogen (i.e., Mtb load). We hypothesized that besides that, the inflammation intensity may depend on the reactivity of the host to the same pathogen load. To address this hypothesis, we re-analyzed our results obtained in F2 mice, by taking into account Mtb colonization data from each individual F2 mouse. The mice were divided into several groups, each group containing mice with similar Mtb loads (less than 3.3-fold differences), and the relative cytokine and chemokine expression was analyzed within each group. We found that despite similar Mtb loads, mice from each group displayed significant variability in the degree of wasting, and in the levels of inflammatory cytokine and chemokine expression (see Figure 4, for examples). In groups that included relatively high numbers of mice (n = 10 and more), a direct correlation between wasting and the expression of IL-1β and IL-11 was detected (Table 3). Correlations between wasting and lung expression of TNF-α, CCL3, and CXCL2 were different (i.e., positive, negative, or insignificant) depending on the selected group of mice, findings which likely mirrored the dual role for these cytokines in TB protection/TB pathology. In none of the analyzed groups was wasting correlated with Mtb load or the expression of iNOS.


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 exhibiting similar mycobacterial loads display different rates of TB progression that positively correlate with the lung inflammatory response.F2 mice challenged with Mtb were divided into several groups, each having similar Mtb loads. Correlations between wasting, mycobacterial load, and cytokine/chemokine expression in mice with lung mycobacterial burdens ranging from 3.3×107 to 1×108 CFUs/lobe are shown (for Spearman correlation coefficients and p-values see Table 3).
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2864263&req=5

pone-0010469-g004: F2 mice exhibiting similar mycobacterial loads display different rates of TB progression that positively correlate with the lung inflammatory response.F2 mice challenged with Mtb were divided into several groups, each having similar Mtb loads. Correlations between wasting, mycobacterial load, and cytokine/chemokine expression in mice with lung mycobacterial burdens ranging from 3.3×107 to 1×108 CFUs/lobe are shown (for Spearman correlation coefficients and p-values see Table 3).
Mentions: There is no doubt that the host inflammatory reaction is driven by pathogen-derived signals [21], [22], and that the intensity of the inflammatory response depends on the quantity of pathogen (i.e., Mtb load). We hypothesized that besides that, the inflammation intensity may depend on the reactivity of the host to the same pathogen load. To address this hypothesis, we re-analyzed our results obtained in F2 mice, by taking into account Mtb colonization data from each individual F2 mouse. The mice were divided into several groups, each group containing mice with similar Mtb loads (less than 3.3-fold differences), and the relative cytokine and chemokine expression was analyzed within each group. We found that despite similar Mtb loads, mice from each group displayed significant variability in the degree of wasting, and in the levels of inflammatory cytokine and chemokine expression (see Figure 4, for examples). In groups that included relatively high numbers of mice (n = 10 and more), a direct correlation between wasting and the expression of IL-1β and IL-11 was detected (Table 3). Correlations between wasting and lung expression of TNF-α, CCL3, and CXCL2 were different (i.e., positive, negative, or insignificant) depending on the selected group of mice, findings which likely mirrored the dual role for these cytokines in TB protection/TB pathology. In none of the analyzed groups was wasting correlated with Mtb load or the expression of iNOS.

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