Figure 9. A model illustrating the linkages between Mtb-infection, foam cell formation and accumulation of caseum in the human TB granuloma.

1. Intracellular Mtb bacilli synthesize and release cell wall components inside their host cells. We have demonstrated previously that these lipids accumulate in the internal vesicles in multi-vesicular bodies, which are exocytosed from the cell in vesicular form.
2. Because of the release of these vesicles, both infected and uninfected macrophages are exposed to cell wall mycolates and induced to form foamy macrophages, as illustrated in Fig 7. The foamy macrophages have been shown to support the maintenance and growth of persistent bacteria.
3. We now propose that these cells die via an inflammatory, necrotic process and release their lipid droplets into the extracellular milieu within the granuloma. As a result of the fibrotic capsule, the human granuloma is an enclosed, isolated structure with minimal vasculature. The enclosed nature of the human granuloma leads to accumulation of necrotic debris as caseum. In this model, this process is an integral part of the pathology that leads to active disease and transmission.