represents early events in the evolution of foamy macrophages in which increased bacterial replication and resultant macrophage necrosis favor the spread of bacteria and the establishment of active disease. During the chronic stages of disease amidst high oxidative stress state in guinea pigs, mycobacteria exposed to low oxygen concentrations may become less metabolically active and persist in a non-replicating state within the foamy macrophages. It is not clear whether activated foamy macrophages take up non-replicating bacteria within the granuloma or bacteria become non-replicating once taken up by cells in chronic stages of infection. Further studies are needed to address this question. One reason for increased bacterial survival in our in-vitro model is potential decreased bactericidal activity of the foamy macrophag- es. Evolution of foamy macrophages is likely a long-term process in which increasing amounts of host lipids accumulate within persistent lesions. 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