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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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Suggested roles for antibacterial and inflammatory responses in the determination of TB outcome.In hosts with deficiency in antibacterial immune response, progressive Mtb growth induces extremely severe TB. In hosts able to eradicate Mtb, no disease is developed. In hosts who are able to restrict Mtb growth but fail to completely eradicate the infection, the outcome depends on quantitatively- and genetically-determined peculiarities of inflammatory response.
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pone-0010469-g008: Suggested roles for antibacterial and inflammatory responses in the determination of TB outcome.In hosts with deficiency in antibacterial immune response, progressive Mtb growth induces extremely severe TB. In hosts able to eradicate Mtb, no disease is developed. In hosts who are able to restrict Mtb growth but fail to completely eradicate the infection, the outcome depends on quantitatively- and genetically-determined peculiarities of inflammatory response.

Mentions: We find that in immunocompetent hosts TB progression is not a direct consequence of high Mtb loads, but rather, is a result of excessive inflammatory reaction developed in Mtb infected lungs. This is supported by the following observations. First, not all F2 mice with high mycobacterial burden in the lungs rapidly progressed to fatal infection. In most mice, the rate of TB progression did not depend on bacterial burden. Second, TB progression did not correlate with lung expression of factors involved in antibacterial response (iNOS, IFN-γ), but correlated with lung expression of factors involved in the development of inflammation (IL-1β, CXCL2, IL-11 et al.). Third, only one of the three QTLs involved in the control of TB severity in F2 mice, was implicated in the control of Mtb colonization in these mice. Our results correspond well to the study of Kramnik's group [19], which showed that differences in TB susceptibility between sst-1 congenic mice did not depend on iNOS/NO production, but rather, were associated with the development of necrotic lung inflammation. Similarly, Bishai et al [25] demonstrated that immunopathology and lethality of TB did not depend on the capacity of mycobacteria to grow and survive in infected host. These reports, together with the results of our study, strongly indicate that host capacity to restrict Mtb growth is not the sole (and likely not the major) factor that determines TB outcome. Our view on the roles that antibacterial and inflammatory responses may play in the determination of TB outcome is presented on Figure 8.


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)

Suggested roles for antibacterial and inflammatory responses in the determination of TB outcome.In hosts with deficiency in antibacterial immune response, progressive Mtb growth induces extremely severe TB. In hosts able to eradicate Mtb, no disease is developed. In hosts who are able to restrict Mtb growth but fail to completely eradicate the infection, the outcome depends on quantitatively- and genetically-determined peculiarities of inflammatory response.
© Copyright Policy
Related In: Results  -  Collection

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

pone-0010469-g008: Suggested roles for antibacterial and inflammatory responses in the determination of TB outcome.In hosts with deficiency in antibacterial immune response, progressive Mtb growth induces extremely severe TB. In hosts able to eradicate Mtb, no disease is developed. In hosts who are able to restrict Mtb growth but fail to completely eradicate the infection, the outcome depends on quantitatively- and genetically-determined peculiarities of inflammatory response.
Mentions: We find that in immunocompetent hosts TB progression is not a direct consequence of high Mtb loads, but rather, is a result of excessive inflammatory reaction developed in Mtb infected lungs. This is supported by the following observations. First, not all F2 mice with high mycobacterial burden in the lungs rapidly progressed to fatal infection. In most mice, the rate of TB progression did not depend on bacterial burden. Second, TB progression did not correlate with lung expression of factors involved in antibacterial response (iNOS, IFN-γ), but correlated with lung expression of factors involved in the development of inflammation (IL-1β, CXCL2, IL-11 et al.). Third, only one of the three QTLs involved in the control of TB severity in F2 mice, was implicated in the control of Mtb colonization in these mice. Our results correspond well to the study of Kramnik's group [19], which showed that differences in TB susceptibility between sst-1 congenic mice did not depend on iNOS/NO production, but rather, were associated with the development of necrotic lung inflammation. Similarly, Bishai et al [25] demonstrated that immunopathology and lethality of TB did not depend on the capacity of mycobacteria to grow and survive in infected host. These reports, together with the results of our study, strongly indicate that host capacity to restrict Mtb growth is not the sole (and likely not the major) factor that determines TB outcome. Our view on the roles that antibacterial and inflammatory responses may play in the determination of TB outcome is presented on Figure 8.

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