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Comparative Study
, 71 (10), 5845-54

Widespread Bronchogenic Dissemination Makes DBA/2 Mice More Susceptible Than C57BL/6 Mice to Experimental Aerosol Infection With Mycobacterium Tuberculosis

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Comparative Study

Widespread Bronchogenic Dissemination Makes DBA/2 Mice More Susceptible Than C57BL/6 Mice to Experimental Aerosol Infection With Mycobacterium Tuberculosis

Pere-Joan Cardona et al. Infect Immun.

Abstract

We have used the murine model of aerosol-induced experimental tuberculosis to assess the effects of four clinical isolates and a reference strain of Mycobacterium tuberculosis on resistant C57BL/6 mice and susceptible DBA/2 mice. Histological studies and detection of 25 cytokines potentially involved in the infection were carried out. DBA/2 mice showed higher concentrations of bacilli in bronchoalveolar lavage fluid and lung tissue. Furthermore, these mice evidenced a larger granulomatous infiltration in the parenchyma due to an increased rate of emigration of infected foamy macrophages from the granulomas to the neighboring pulmonary alveolar spaces. The better control of bacillary concentrations and pulmonary infiltration observed in C57BL/6 mice from week 3 postinfection could result from their higher RANTES, ICAM-1, and gamma interferon (IFN-gamma) mRNA levels. On the other hand, the higher MIP-2 and MCP-3 mRNA levels seen in DBA/2 mice would result in stronger lung recruitment of macrophages and neutrophils. Additionally, DBA/2 mice showed increased inducible nitric oxide synthase expression, induced by the larger number of foamy macrophages, at weeks 18 and 22. This increment was a consequence of phagocytosed bacillary debris, was independent of IFN-gamma expression, and could exert only a bacteriostatic effect. The results of the study suggest that DBA/2 mice are more susceptible than C57BL/6 mice to M. tuberculosis infection due to a higher bronchial dissemination of bacilli inside poorly activated foamy macrophages.

Figures

FIG. 1.
FIG. 1.
Evolution of BAL fluid, lung, and spleen bacillary concentrations for each isolate. Data are log10 CFU obtained for each isolate, expressed as means ± standard deviations for four mice. Open and filled symbols, DBA/2 and C57BL/6 mice, respectively. Differences between means were compared using the Student's t test. Asterisks indicate significant differences (P < 0.05).
FIG. 2.
FIG. 2.
Evolution of granulomatous infiltration in the lungs. Data are percentages calculated by dividing the granuloma-involved area by the global tissue area and multiplying by 100. Two lung lobes were analyzed for each mouse. Open and filled symbols, DBA/2 and C57BL/6 mice, respectively. Linear regressions were determined by the Pearson product moment correlation coefficient (P < 0.05 in all cases).
FIG. 3.
FIG. 3.
Evolution of infiltration in C57BL/6 (A through D) and DBA/2 (E through H) mice infected with isolate UTE 0423R at weeks 3 (A and E), 9 (B and F), 18 (C and G), and 22 (D and H) postinfection. Microphotographs were taken with a Nikon stereoscopic microscope SMZ800 (Nikon) at a magnification of ×10. Bar, 500 μm.
FIG. 4.
FIG. 4.
Evolution of granulomas in C57BL/6 (A through D) and DBA/2 (E through H) mice infected with isolate UTE 0423R at weeks 9 (A through C and E through G) and 22 (D and H) postinfection. (A, B, E, and F) Primary granulomas, with a center of infected macrophages and a mantle of lymphocytes. Panels B and F show intragranulomatous necrosis at a higher power (×400). The asterisk in panel A marks the zone amplified in panel B. (C and G) Secondary and tertiary granulomas, respectively, with a compact center of lymphocytes admixed with scanty infected macrophages. In panel G two secondary granulomas are surrounded by a layer of foamy macrophages that connects them both. (D and H) Tertiary granulomas, with septal thickening of alveoli filled with foamy macrophages. All microphotographs except those in panels B and E were taken at a magnification of ×100. Bars, 100 μm.
FIG. 5.
FIG. 5.
Fibrosis and inflammation at weeks 9 (A and C) and 18 (B and D) postinfection in C57BL/6 (A and B) and DBA/2 (C and D) mice infected with isolate UTE 0423R. Microphotographs were taken at a magnification of ×200. Bars, 100 μm. Asterisks mark granuloma centers. Black arrow indicates cholesterol crystals; white arrows point to foamy macrophages.
FIG. 6.
FIG. 6.
Evolution of mRNA expression of the chemokines and cytokines that were differently expressed by the two mouse strains, and of iNOS. Results for the most representative M. tuberculosis isolates (UTE 0423R, UTE 0335R, and H37Rv) are presented as averages and standard deviations of the ratio of the expression of each particular chemokine or cytokine to that of HPRT in the corresponding sample. Open and filled symbols, DBA/2 and C57BL/6 mice, respectively. The difference between means was determined using Student's t test. Asterisks indicate significant differences (P < 0.05).
FIG. 7.
FIG. 7.
Immunohistochemistry. Shown is macrophage immunolocalization of iNOS (A and C) and the 38-kDa M. tuberculosis cell wall antigen (B and D) in C57BL/6 (A and B) and DBA/2 (C and D) mice infected with isolate UTE 0423R (week 22 postinfection). Microphotographs were taken at a magnification of ×400. Bars, 50 μm. Asterisks mark granuloma centers.

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