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Early specific host response associated with starting effective tuberculosis treatment in an infection controlled placebo controlled mouse study.

den Hertog AL, de Vos AF, Klatser PR, Anthony RM - PLoS ONE (2013)

Bottom Line: Serum was collected prior to and during the first 3 weeks of isoniazid (INH) and rifampicin (RIF) chemotherapy, and levels of 23 selected cytokines/chemokines were measured using a liquid bead array.In infected mice, IFNγ, IP-10, MIG and MCP-1 levels decreased within 7 days of treatment with RIF+INH compared to placebo.Thus, IFNγ, IP-10, MIG and MCP-1 are promising 'Treat-to-Test' targets for the diagnosis of TB and deserve further investigation in a study on human TB suspects.

View Article: PubMed Central - PubMed

Affiliation: Royal Tropical Institute, KIT Biomedical Research, Amsterdam, The Netherlands.

ABSTRACT
Recently we proposed exploring the potential of treatment stimulated testing as diagnostic method for tuberculosis (TB). An infection controlled placebo controlled mouse study was performed to investigate whether serum cytokine levels changed measurably during the early phase of TB chemotherapy. Serum was collected prior to and during the first 3 weeks of isoniazid (INH) and rifampicin (RIF) chemotherapy, and levels of 23 selected cytokines/chemokines were measured using a liquid bead array. The serum levels of IFNγ, IP-10, MIG, MCP-1, IL-17 and IL-6 were elevated in the TB infected mice compared to non-infected mice at least at 1 time point measured. In infected mice, IFNγ, IP-10, MIG and MCP-1 levels decreased within 7 days of treatment with RIF+INH compared to placebo. Treatment of non-infected mice in the absence of tuberculosis infection had no effect on these cytokines. IL-17 and IL-6 had decreased to baseline in all infected mice prior to the initiation of treatment. This study demonstrates that systemic levels of some cytokines, more specifically IFNγ, IP-10, MIG and MCP-1, rapidly and specifically change upon starting TB chemotherapy only in the presence of infection in a mouse model. Thus, IFNγ, IP-10, MIG and MCP-1 are promising 'Treat-to-Test' targets for the diagnosis of TB and deserve further investigation in a study on human TB suspects.

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Lung CFU and relative lung weights of mice.A: Relative lung weights were calculated as a percentage of total body mass (mean +− SE). Black squares: uninfected placebo, open squares: uninfected RIF+INH treated, black circles: infected placebo, open circles: infected RIF+INH treated mice. At start of treatment, relative lung weights were increased in infected mice compared to uninfected mice (p<0.001). After an initial increase within 3 days, relative lung weight started to decrease within 3–7 days after start of treatment with RIF+INH in the infected mice although remaining higher than in the uninfected mice until the end of the experiment (p<0.01). Treatment had no effect on lung weight in uninfected mice. B: CFU counts of lung homogenates of sacrificed mice. Median baseline level in infected mice prior to treatment was 1.3×106CFU per lung (black squares) and similar levels were found after 7 and 21 days of placebo treatment (black circles, 3 days not available due to contamination of culture plates). Treatment with RIF+INH strongly reduced CFU counts within 7 days (open circles; detection limit 2×103 CFU/lung). Counts from 1 mouse are not available due to contamination. Cultures of undiluted lung homogenates from uninfected mice yielded no TB colonies (not shown). ** p<0.01
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pone-0057997-g001: Lung CFU and relative lung weights of mice.A: Relative lung weights were calculated as a percentage of total body mass (mean +− SE). Black squares: uninfected placebo, open squares: uninfected RIF+INH treated, black circles: infected placebo, open circles: infected RIF+INH treated mice. At start of treatment, relative lung weights were increased in infected mice compared to uninfected mice (p<0.001). After an initial increase within 3 days, relative lung weight started to decrease within 3–7 days after start of treatment with RIF+INH in the infected mice although remaining higher than in the uninfected mice until the end of the experiment (p<0.01). Treatment had no effect on lung weight in uninfected mice. B: CFU counts of lung homogenates of sacrificed mice. Median baseline level in infected mice prior to treatment was 1.3×106CFU per lung (black squares) and similar levels were found after 7 and 21 days of placebo treatment (black circles, 3 days not available due to contamination of culture plates). Treatment with RIF+INH strongly reduced CFU counts within 7 days (open circles; detection limit 2×103 CFU/lung). Counts from 1 mouse are not available due to contamination. Cultures of undiluted lung homogenates from uninfected mice yielded no TB colonies (not shown). ** p<0.01

Mentions: To confirm successful infection, TB lung counts of 2 mice sacrificed 1 day after the infection were performed, yielding ∼180 CFU/lung. Furthermore, levels around 106 to 107 TB CFU per lung as well as an increase in lung weight relative to body weight (‘relative lung weight’) were detected in all infected mice sacrificed before treatment and in placebo groups (p<0.0001; Figure 1).


Early specific host response associated with starting effective tuberculosis treatment in an infection controlled placebo controlled mouse study.

den Hertog AL, de Vos AF, Klatser PR, Anthony RM - PLoS ONE (2013)

Lung CFU and relative lung weights of mice.A: Relative lung weights were calculated as a percentage of total body mass (mean +− SE). Black squares: uninfected placebo, open squares: uninfected RIF+INH treated, black circles: infected placebo, open circles: infected RIF+INH treated mice. At start of treatment, relative lung weights were increased in infected mice compared to uninfected mice (p<0.001). After an initial increase within 3 days, relative lung weight started to decrease within 3–7 days after start of treatment with RIF+INH in the infected mice although remaining higher than in the uninfected mice until the end of the experiment (p<0.01). Treatment had no effect on lung weight in uninfected mice. B: CFU counts of lung homogenates of sacrificed mice. Median baseline level in infected mice prior to treatment was 1.3×106CFU per lung (black squares) and similar levels were found after 7 and 21 days of placebo treatment (black circles, 3 days not available due to contamination of culture plates). Treatment with RIF+INH strongly reduced CFU counts within 7 days (open circles; detection limit 2×103 CFU/lung). Counts from 1 mouse are not available due to contamination. Cultures of undiluted lung homogenates from uninfected mice yielded no TB colonies (not shown). ** p<0.01
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3585278&req=5

pone-0057997-g001: Lung CFU and relative lung weights of mice.A: Relative lung weights were calculated as a percentage of total body mass (mean +− SE). Black squares: uninfected placebo, open squares: uninfected RIF+INH treated, black circles: infected placebo, open circles: infected RIF+INH treated mice. At start of treatment, relative lung weights were increased in infected mice compared to uninfected mice (p<0.001). After an initial increase within 3 days, relative lung weight started to decrease within 3–7 days after start of treatment with RIF+INH in the infected mice although remaining higher than in the uninfected mice until the end of the experiment (p<0.01). Treatment had no effect on lung weight in uninfected mice. B: CFU counts of lung homogenates of sacrificed mice. Median baseline level in infected mice prior to treatment was 1.3×106CFU per lung (black squares) and similar levels were found after 7 and 21 days of placebo treatment (black circles, 3 days not available due to contamination of culture plates). Treatment with RIF+INH strongly reduced CFU counts within 7 days (open circles; detection limit 2×103 CFU/lung). Counts from 1 mouse are not available due to contamination. Cultures of undiluted lung homogenates from uninfected mice yielded no TB colonies (not shown). ** p<0.01
Mentions: To confirm successful infection, TB lung counts of 2 mice sacrificed 1 day after the infection were performed, yielding ∼180 CFU/lung. Furthermore, levels around 106 to 107 TB CFU per lung as well as an increase in lung weight relative to body weight (‘relative lung weight’) were detected in all infected mice sacrificed before treatment and in placebo groups (p<0.0001; Figure 1).

Bottom Line: Serum was collected prior to and during the first 3 weeks of isoniazid (INH) and rifampicin (RIF) chemotherapy, and levels of 23 selected cytokines/chemokines were measured using a liquid bead array.In infected mice, IFNγ, IP-10, MIG and MCP-1 levels decreased within 7 days of treatment with RIF+INH compared to placebo.Thus, IFNγ, IP-10, MIG and MCP-1 are promising 'Treat-to-Test' targets for the diagnosis of TB and deserve further investigation in a study on human TB suspects.

View Article: PubMed Central - PubMed

Affiliation: Royal Tropical Institute, KIT Biomedical Research, Amsterdam, The Netherlands.

ABSTRACT
Recently we proposed exploring the potential of treatment stimulated testing as diagnostic method for tuberculosis (TB). An infection controlled placebo controlled mouse study was performed to investigate whether serum cytokine levels changed measurably during the early phase of TB chemotherapy. Serum was collected prior to and during the first 3 weeks of isoniazid (INH) and rifampicin (RIF) chemotherapy, and levels of 23 selected cytokines/chemokines were measured using a liquid bead array. The serum levels of IFNγ, IP-10, MIG, MCP-1, IL-17 and IL-6 were elevated in the TB infected mice compared to non-infected mice at least at 1 time point measured. In infected mice, IFNγ, IP-10, MIG and MCP-1 levels decreased within 7 days of treatment with RIF+INH compared to placebo. Treatment of non-infected mice in the absence of tuberculosis infection had no effect on these cytokines. IL-17 and IL-6 had decreased to baseline in all infected mice prior to the initiation of treatment. This study demonstrates that systemic levels of some cytokines, more specifically IFNγ, IP-10, MIG and MCP-1, rapidly and specifically change upon starting TB chemotherapy only in the presence of infection in a mouse model. Thus, IFNγ, IP-10, MIG and MCP-1 are promising 'Treat-to-Test' targets for the diagnosis of TB and deserve further investigation in a study on human TB suspects.

Show MeSH
Related in: MedlinePlus