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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

Molecular profiles of lung, and of blood and plasma in M.-tuberculosis-infected mice. Female 8-week-old non-sibling DO mice (N=166) and C57BL/6J (N=10) mice were infected with ∼100 M. tuberculosis (M.tb) bacilli by aerosol. Cytokines and chemokines were quantified in homogenized lung. Blood cytokines (IL-2, IFN-γ, IL-12, TNF, IL-10) were quantified after stimulation with antigen. Neutrophil chemokines (CXCL1, CXCL5) were quantified in plasma, but CXCL2 was not detectable. From right to left, molecular features are grouped as follows: T-cell cytokines (IL-2, IFN-γ), macrophage cytokines (IL-12, TNF, IL-10) and neutrophil chemokines (CXCL1, CXCL5, CXCL2). Each dot represents the average of duplicate or triplicate samples from one mouse. The y-axes are defined at the bottom of the figure. Data are combined from two independent experiments.
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DMM020867F3: Molecular profiles of lung, and of blood and plasma in M.-tuberculosis-infected mice. Female 8-week-old non-sibling DO mice (N=166) and C57BL/6J (N=10) mice were infected with ∼100 M. tuberculosis (M.tb) bacilli by aerosol. Cytokines and chemokines were quantified in homogenized lung. Blood cytokines (IL-2, IFN-γ, IL-12, TNF, IL-10) were quantified after stimulation with antigen. Neutrophil chemokines (CXCL1, CXCL5) were quantified in plasma, but CXCL2 was not detectable. From right to left, molecular features are grouped as follows: T-cell cytokines (IL-2, IFN-γ), macrophage cytokines (IL-12, TNF, IL-10) and neutrophil chemokines (CXCL1, CXCL5, CXCL2). Each dot represents the average of duplicate or triplicate samples from one mouse. The y-axes are defined at the bottom of the figure. Data are combined from two independent experiments.

Mentions: Fig. 3 depicts the cytokine and chemokine data for each class of DO mice (supersusceptible, susceptible, resistant and non-infected) and for the C57BL/6J founder strain for comparison. Using data from infected DO mice, the following chemokines and cytokines were tested for correlations with disease indicators (percentage of peak body weight at euthanasia, bacterial burden, survival): lung, blood and plasma. Lastly, lung and blood and plasma cytokines and chemokines were correlated with each other. Lung cytokine and chemokine correlations with disease indicators are shown in Table 1 [percentage of peak body weight at euthanasia and M. tuberculosis colony-forming units (CFU)]. Lung cytokine and chemokine correlations with survival were nearly identical to those for the other indicators (not shown). Statistically significant, very strong or strong disease correlates in DO mouse lungs were dead cells, CXCL1, CXCL2, CXCL5 and TNF, which supports previous studies from inbred mice and humans (Bekker et al., 2000; Gopal et al., 2013; Nouailles et al., 2014). Lung cytokines (IFN-γ, IL-2, IL-12, IL-10) were weak correlates of disease with variable statistical significance.Fig. 3.


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)

Molecular profiles of lung, and of blood and plasma in M.-tuberculosis-infected mice. Female 8-week-old non-sibling DO mice (N=166) and C57BL/6J (N=10) mice were infected with ∼100 M. tuberculosis (M.tb) bacilli by aerosol. Cytokines and chemokines were quantified in homogenized lung. Blood cytokines (IL-2, IFN-γ, IL-12, TNF, IL-10) were quantified after stimulation with antigen. Neutrophil chemokines (CXCL1, CXCL5) were quantified in plasma, but CXCL2 was not detectable. From right to left, molecular features are grouped as follows: T-cell cytokines (IL-2, IFN-γ), macrophage cytokines (IL-12, TNF, IL-10) and neutrophil chemokines (CXCL1, CXCL5, CXCL2). Each dot represents the average of duplicate or triplicate samples from one mouse. The y-axes are defined at the bottom of the figure. Data are combined from two independent experiments.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

DMM020867F3: Molecular profiles of lung, and of blood and plasma in M.-tuberculosis-infected mice. Female 8-week-old non-sibling DO mice (N=166) and C57BL/6J (N=10) mice were infected with ∼100 M. tuberculosis (M.tb) bacilli by aerosol. Cytokines and chemokines were quantified in homogenized lung. Blood cytokines (IL-2, IFN-γ, IL-12, TNF, IL-10) were quantified after stimulation with antigen. Neutrophil chemokines (CXCL1, CXCL5) were quantified in plasma, but CXCL2 was not detectable. From right to left, molecular features are grouped as follows: T-cell cytokines (IL-2, IFN-γ), macrophage cytokines (IL-12, TNF, IL-10) and neutrophil chemokines (CXCL1, CXCL5, CXCL2). Each dot represents the average of duplicate or triplicate samples from one mouse. The y-axes are defined at the bottom of the figure. Data are combined from two independent experiments.
Mentions: Fig. 3 depicts the cytokine and chemokine data for each class of DO mice (supersusceptible, susceptible, resistant and non-infected) and for the C57BL/6J founder strain for comparison. Using data from infected DO mice, the following chemokines and cytokines were tested for correlations with disease indicators (percentage of peak body weight at euthanasia, bacterial burden, survival): lung, blood and plasma. Lastly, lung and blood and plasma cytokines and chemokines were correlated with each other. Lung cytokine and chemokine correlations with disease indicators are shown in Table 1 [percentage of peak body weight at euthanasia and M. tuberculosis colony-forming units (CFU)]. Lung cytokine and chemokine correlations with survival were nearly identical to those for the other indicators (not shown). Statistically significant, very strong or strong disease correlates in DO mouse lungs were dead cells, CXCL1, CXCL2, CXCL5 and TNF, which supports previous studies from inbred mice and humans (Bekker et al., 2000; Gopal et al., 2013; Nouailles et al., 2014). Lung cytokines (IFN-γ, IL-2, IL-12, IL-10) were weak correlates of disease with variable statistical significance.Fig. 3.

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