Journal
TUBERCULOSIS
Volume 92, Issue 2, Pages 160-165Publisher
CHURCHILL LIVINGSTONE
DOI: 10.1016/j.tube.2011.11.007
Keywords
Aerosol; Animal model; Median infectious dose; Mycobacterium tuberculosis
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Funding
- National Institute of Health, Southeast Regional Center of Excellence for Emerging Infections and Biodefense [U54 AI057157]
- Duke Center for Translational Research [P30 AI051445]
- Regional Biocontainment Laboratory at Duke [UC6 AI058607]
- National Science Foundation [2011083676]
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A murine low dose (LD) aerosol model is commonly used to test tuberculosis vaccines. Doses of 50-400 CFU (24 h lung CFU) infect 100% of exposed mice. The LD model measures progression from infection to disease based on organ CFU at defined time points. To mimic natural exposure, we exposed mice to an ultra-low dose (ULD) aerosol. We estimated the presented dose by sampling the aerosol. Female C57BL/6 mice were exposed to Mycobacterium tuberculosis H37Rv aerosol at 1.0, 1.1, 1.6, 5.4, and 11 CFU presented dose, infecting 27%, 36%, 36%, 100%, and 95% of mice, respectively. These data are compatible with a stochastic infection event (Poisson distribution, weighted R-2 = 0.97) or with a doseeresponse relationship (sigmoid distribution, weighted R-2 = 0.97). Based on the later assumption, the ID50 was 1.6 CFU presented dose (95% confidence interval, 1.2-2.1). We compared organ CFU after ULD and LD aerosols (5.4 vs. 395 CFU presented dose). Lung burden was 30-fold lower in the ULD model at 4 weeks (3.4 vs. 4.8 logs, p < 0.001) and 18 weeks (<= 3.6 vs. 5.0 logs, p = 0.01). Mice exposed to ULD aerosols as compared to LD aerosols had greater within-group CFU variability. Exposure to ULD aerosols leads to infection in a subset of mice, and to persistently low organ CFU. The ULD aerosol model may resemble human pulmonary tuberculosis more closely than the standard LD model, and may be used to identify host or bacterial factors that modulate the initial infection event. (C) 2011 Elsevier Ltd. All rights reserved.
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