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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

Lung lesions in M.-tuberculosis-infected DO mice. Female 8-week-old non-sibling DO mice (N=97) were infected with ∼100 M. tuberculosis (M.tb) bacilli by using an aerosol. Representative hematoxylin and eosin (H&E)-stained lung sections are shown. Supersusceptible (A) with inset showing substantial lung tissue, macrophage and neutrophil necrosis with capillary thrombosis magnified (B); susceptible (C) with inset showing a small region of necrosis surrounded by inflammatory cells that lacks thrombosis (D); resistant (E) with inset showing a small, non-necrotic lesion with an abundance of perivascular lymphocytes (F). Black lines surround neutrophils in alveolar spaces (G) and within macrophage-rich granulomas (H). Magnifications are 10× (A,C,E); 200× (B,D,F); and 400× (G,H). Two lung lobes from each mouse were scored for relative severity of each lesion type by a board-certified veterinary pathologist (G.B.) without knowledge of the groups, and the data was compiled (I).
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DMM020867F2: Lung lesions in M.-tuberculosis-infected DO mice. Female 8-week-old non-sibling DO mice (N=97) were infected with ∼100 M. tuberculosis (M.tb) bacilli by using an aerosol. Representative hematoxylin and eosin (H&E)-stained lung sections are shown. Supersusceptible (A) with inset showing substantial lung tissue, macrophage and neutrophil necrosis with capillary thrombosis magnified (B); susceptible (C) with inset showing a small region of necrosis surrounded by inflammatory cells that lacks thrombosis (D); resistant (E) with inset showing a small, non-necrotic lesion with an abundance of perivascular lymphocytes (F). Black lines surround neutrophils in alveolar spaces (G) and within macrophage-rich granulomas (H). Magnifications are 10× (A,C,E); 200× (B,D,F); and 400× (G,H). Two lung lobes from each mouse were scored for relative severity of each lesion type by a board-certified veterinary pathologist (G.B.) without knowledge of the groups, and the data was compiled (I).

Mentions: It is common in human TB studies to stratify individuals by using clinical symptoms or disease severity, and we applied this approach to DO mice. Three susceptibility classes were detected during infection – supersusceptible, susceptible and resistant. Fig. 1C,D show that supersusceptible mice lost the most body weight and had the highest lung bacterial burdens; susceptible mice were intermediate for both; and resistant mice exhibited the lowest values for both. Fig. 2 shows common lung lesions for each susceptibility class. The lungs of supersusceptible DO mice typically contained large lesions, occupying approximately 75% of lung tissue, which were effaced by coalescing foci with central coagulation necrosis of lung alveolar septae and intra-alveolar macrophages [resembling caseous necrosis (Leong et al., 2011; Marzo et al., 2014) and necrotizing tuberculous pneumonia (Hunter, 2011)], often with a peripheral rim of thrombosed septal capillaries and intra-alveolar neutrophilic debris. By contrast, the lungs of resistant mice typically contained small granulomas, occupying approximately 25-50% of lung tissue, comprising macrophages and abundant perivascular lymphocytes, but little necrosis or neutrophils, resembling the M.-tuberculosis-resistant C57BL/6 founder strain (Vesosky et al., 2010; Niazi et al., 2014). Susceptible DO mice showed intermediate patterns with small regions of coagulation and/or caseous necrosis that were surrounded by mixed inflammatory cells (macrophages, lymphocytes, neutrophils), but lacked thrombosis.Fig. 2.


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)

Lung lesions in M.-tuberculosis-infected DO mice. Female 8-week-old non-sibling DO mice (N=97) were infected with ∼100 M. tuberculosis (M.tb) bacilli by using an aerosol. Representative hematoxylin and eosin (H&E)-stained lung sections are shown. Supersusceptible (A) with inset showing substantial lung tissue, macrophage and neutrophil necrosis with capillary thrombosis magnified (B); susceptible (C) with inset showing a small region of necrosis surrounded by inflammatory cells that lacks thrombosis (D); resistant (E) with inset showing a small, non-necrotic lesion with an abundance of perivascular lymphocytes (F). Black lines surround neutrophils in alveolar spaces (G) and within macrophage-rich granulomas (H). Magnifications are 10× (A,C,E); 200× (B,D,F); and 400× (G,H). Two lung lobes from each mouse were scored for relative severity of each lesion type by a board-certified veterinary pathologist (G.B.) without knowledge of the groups, and the data was compiled (I).
© Copyright Policy - open-access
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4582107&req=5

DMM020867F2: Lung lesions in M.-tuberculosis-infected DO mice. Female 8-week-old non-sibling DO mice (N=97) were infected with ∼100 M. tuberculosis (M.tb) bacilli by using an aerosol. Representative hematoxylin and eosin (H&E)-stained lung sections are shown. Supersusceptible (A) with inset showing substantial lung tissue, macrophage and neutrophil necrosis with capillary thrombosis magnified (B); susceptible (C) with inset showing a small region of necrosis surrounded by inflammatory cells that lacks thrombosis (D); resistant (E) with inset showing a small, non-necrotic lesion with an abundance of perivascular lymphocytes (F). Black lines surround neutrophils in alveolar spaces (G) and within macrophage-rich granulomas (H). Magnifications are 10× (A,C,E); 200× (B,D,F); and 400× (G,H). Two lung lobes from each mouse were scored for relative severity of each lesion type by a board-certified veterinary pathologist (G.B.) without knowledge of the groups, and the data was compiled (I).
Mentions: It is common in human TB studies to stratify individuals by using clinical symptoms or disease severity, and we applied this approach to DO mice. Three susceptibility classes were detected during infection – supersusceptible, susceptible and resistant. Fig. 1C,D show that supersusceptible mice lost the most body weight and had the highest lung bacterial burdens; susceptible mice were intermediate for both; and resistant mice exhibited the lowest values for both. Fig. 2 shows common lung lesions for each susceptibility class. The lungs of supersusceptible DO mice typically contained large lesions, occupying approximately 75% of lung tissue, which were effaced by coalescing foci with central coagulation necrosis of lung alveolar septae and intra-alveolar macrophages [resembling caseous necrosis (Leong et al., 2011; Marzo et al., 2014) and necrotizing tuberculous pneumonia (Hunter, 2011)], often with a peripheral rim of thrombosed septal capillaries and intra-alveolar neutrophilic debris. By contrast, the lungs of resistant mice typically contained small granulomas, occupying approximately 25-50% of lung tissue, comprising macrophages and abundant perivascular lymphocytes, but little necrosis or neutrophils, resembling the M.-tuberculosis-resistant C57BL/6 founder strain (Vesosky et al., 2010; Niazi et al., 2014). Susceptible DO mice showed intermediate patterns with small regions of coagulation and/or caseous necrosis that were surrounded by mixed inflammatory cells (macrophages, lymphocytes, neutrophils), but lacked thrombosis.Fig. 2.

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