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Lung necrosis and neutrophils reflect common pathways of susceptibility to Mycobacterium tuberculosis in genetically diverse, immune-competent mice.

Niazi MK, Dhulekar N, Schmidt D, Major S, Cooper R, Abeijon C, Gatti DM, Kramnik I, Yener B, Gurcan M, Beamer G - Dis Model Mech (2015)

Bottom Line: Low to no IFN-γ, IL-12, IL-2 and IL-10 successfully discriminated non-infected mice from infected mice but failed to discriminate disease status amongst supersusceptible, susceptible and resistant M.-tuberculosis-infected DO mice.Additional analyses identified CXCL1 as a promising peripheral biomarker of disease and of CXCL1 production in the lungs.From these results, we conclude that: (1) DO mice respond variably to M. tuberculosis infection and will be useful to identify pathways involving necrosis and neutrophils; (2) data from DO mice is suited for machine learning methods to build, validate and test models with independent data based solely on molecular biomarkers; (3) low levels of immunological cytokines best indicate a lack of exposure to M. tuberculosis but cannot distinguish infection from disease.

View Article: PubMed Central - PubMed

Affiliation: Department of Biomedical Informatics, The Ohio State University, Columbus, 43210 OH, USA.

No MeSH data available.


Related in: MedlinePlus

M. tuberculosis infection and TB disease indicators in mice. Female 8-week-old non-sibling DO mice (N=166) and C57BL/6J mice (N=10) were infected with ∼100 M. tuberculosis (M.tb) bacilli by aerosol. Survival was assessed by euthanasia owing to morbidity or by euthanasia at day 35 of infection, whichever came first. Survival of DO mice compared with that of the parental C57BL/6J strain was analyzed by using a Log-rank test, ****P<0.001 (A). The percentage of peak body weight (BW) and lung M. tuberculosis CFU were strong, significant negative correlations in DO mice (Spearman r −0.79, P<0.001, 95% CI −0.84 to −0.72) (B). The percentage of peak BW (C) and lung M. tuberculosis burden (D) from non-infected, resistant, susceptible and supersusceptible (described in the Materials and Methods) DO mice, and C57BL/6J mice were analyzed by using ANOVA with Tukey's post-test, ****P<0.0001. Data are combined from two independent experimental infections: N=97 DO mice in the first experiment, N=69 DO mice and N=10 C57BL/6J mice in the second experiment.
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DMM020867F1: M. tuberculosis infection and TB disease indicators in mice. Female 8-week-old non-sibling DO mice (N=166) and C57BL/6J mice (N=10) were infected with ∼100 M. tuberculosis (M.tb) bacilli by aerosol. Survival was assessed by euthanasia owing to morbidity or by euthanasia at day 35 of infection, whichever came first. Survival of DO mice compared with that of the parental C57BL/6J strain was analyzed by using a Log-rank test, ****P<0.001 (A). The percentage of peak body weight (BW) and lung M. tuberculosis CFU were strong, significant negative correlations in DO mice (Spearman r −0.79, P<0.001, 95% CI −0.84 to −0.72) (B). The percentage of peak BW (C) and lung M. tuberculosis burden (D) from non-infected, resistant, susceptible and supersusceptible (described in the Materials and Methods) DO mice, and C57BL/6J mice were analyzed by using ANOVA with Tukey's post-test, ****P<0.0001. Data are combined from two independent experimental infections: N=97 DO mice in the first experiment, N=69 DO mice and N=10 C57BL/6J mice in the second experiment.

Mentions: All mice gained weight for at least two weeks following infection with ∼100 M. tuberculosis bacilli (supplementary material Fig. S1). Afterwards, nearly half of the DO mice developed morbidity requiring euthanasia before 35 days, resulting in significantly reduced survival compared to the founder C57BL/6J strain (Fig. 1A). Reduced survival strongly reflected the daily rate of weight loss (not shown), as observed in other heterogeneous mice (Harrison et al., 2014). As expected, the percentage of the peak body weight at euthanasia and lung M. tuberculosis burden had a strong, significant inverse correlation (Fig. 1B) such that high bacterial burden associated with weight loss. Interestingly, these effects were independent of absolute body weight before infection or at peak body weight (not shown). Thus, body weight alone does not appear to protect against TB.Fig. 1.


Lung necrosis and neutrophils reflect common pathways of susceptibility to Mycobacterium tuberculosis in genetically diverse, immune-competent mice.

Niazi MK, Dhulekar N, Schmidt D, Major S, Cooper R, Abeijon C, Gatti DM, Kramnik I, Yener B, Gurcan M, Beamer G - Dis Model Mech (2015)

M. tuberculosis infection and TB disease indicators in mice. Female 8-week-old non-sibling DO mice (N=166) and C57BL/6J mice (N=10) were infected with ∼100 M. tuberculosis (M.tb) bacilli by aerosol. Survival was assessed by euthanasia owing to morbidity or by euthanasia at day 35 of infection, whichever came first. Survival of DO mice compared with that of the parental C57BL/6J strain was analyzed by using a Log-rank test, ****P<0.001 (A). The percentage of peak body weight (BW) and lung M. tuberculosis CFU were strong, significant negative correlations in DO mice (Spearman r −0.79, P<0.001, 95% CI −0.84 to −0.72) (B). The percentage of peak BW (C) and lung M. tuberculosis burden (D) from non-infected, resistant, susceptible and supersusceptible (described in the Materials and Methods) DO mice, and C57BL/6J mice were analyzed by using ANOVA with Tukey's post-test, ****P<0.0001. Data are combined from two independent experimental infections: N=97 DO mice in the first experiment, N=69 DO mice and N=10 C57BL/6J mice in the second experiment.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4582107&req=5

DMM020867F1: M. tuberculosis infection and TB disease indicators in mice. Female 8-week-old non-sibling DO mice (N=166) and C57BL/6J mice (N=10) were infected with ∼100 M. tuberculosis (M.tb) bacilli by aerosol. Survival was assessed by euthanasia owing to morbidity or by euthanasia at day 35 of infection, whichever came first. Survival of DO mice compared with that of the parental C57BL/6J strain was analyzed by using a Log-rank test, ****P<0.001 (A). The percentage of peak body weight (BW) and lung M. tuberculosis CFU were strong, significant negative correlations in DO mice (Spearman r −0.79, P<0.001, 95% CI −0.84 to −0.72) (B). The percentage of peak BW (C) and lung M. tuberculosis burden (D) from non-infected, resistant, susceptible and supersusceptible (described in the Materials and Methods) DO mice, and C57BL/6J mice were analyzed by using ANOVA with Tukey's post-test, ****P<0.0001. Data are combined from two independent experimental infections: N=97 DO mice in the first experiment, N=69 DO mice and N=10 C57BL/6J mice in the second experiment.
Mentions: All mice gained weight for at least two weeks following infection with ∼100 M. tuberculosis bacilli (supplementary material Fig. S1). Afterwards, nearly half of the DO mice developed morbidity requiring euthanasia before 35 days, resulting in significantly reduced survival compared to the founder C57BL/6J strain (Fig. 1A). Reduced survival strongly reflected the daily rate of weight loss (not shown), as observed in other heterogeneous mice (Harrison et al., 2014). As expected, the percentage of the peak body weight at euthanasia and lung M. tuberculosis burden had a strong, significant inverse correlation (Fig. 1B) such that high bacterial burden associated with weight loss. Interestingly, these effects were independent of absolute body weight before infection or at peak body weight (not shown). Thus, body weight alone does not appear to protect against TB.Fig. 1.

Bottom Line: Low to no IFN-γ, IL-12, IL-2 and IL-10 successfully discriminated non-infected mice from infected mice but failed to discriminate disease status amongst supersusceptible, susceptible and resistant M.-tuberculosis-infected DO mice.Additional analyses identified CXCL1 as a promising peripheral biomarker of disease and of CXCL1 production in the lungs.From these results, we conclude that: (1) DO mice respond variably to M. tuberculosis infection and will be useful to identify pathways involving necrosis and neutrophils; (2) data from DO mice is suited for machine learning methods to build, validate and test models with independent data based solely on molecular biomarkers; (3) low levels of immunological cytokines best indicate a lack of exposure to M. tuberculosis but cannot distinguish infection from disease.

View Article: PubMed Central - PubMed

Affiliation: Department of Biomedical Informatics, The Ohio State University, Columbus, 43210 OH, USA.

No MeSH data available.


Related in: MedlinePlus