Foamy Macrophages from Tuberculous Patients' Granulomas Constitute a Nutrient-Rich Reservoir for M. tuberculosis Persistence

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Abstract
Tuberculosis (TB) is characterized by a tight interplay between Mycobacterium tuberculosis and host cells within granulomas. These cellular aggregates restrict bacterial spreading, but do not kill all the bacilli, which can persist for years. In-depth investigation of M. tuberculosis interactions with granuloma-specific cell populations are needed to gain insight into mycobacterial persistence, and to better understand the physiopathology of the disease. We have analyzed the formation of foamy macrophages (FMs), a granuloma-specific cell population characterized by its high lipid content, and studied their interaction with the tubercle bacillus. Within our in vitro human granuloma model, M. tuberculosis long chain fatty acids, namely oxygenated mycolic acids (MA), triggered the differentiation of human monocyte-derived macrophages into FMs. In these cells, mycobacteria no longer replicated and switched to a dormant non-replicative state. Electron microscopy observation of M. tuberculosis–infected FMs showed that the mycobacteria-containing phagosomes migrate towards host cell lipid bodies (LB), a process which culminates with the engulfment of the bacillus into the lipid droplets and with the accumulation of lipids within the microbe. Altogether, our results suggest that oxygenated mycolic acids from M. tuberculosis play a crucial role in the differentiation of macrophages into FMs. These cells might constitute a reservoir used by the tubercle bacillus for long-term persistence within its human host, and could provide a relevant model for the screening of new antimicrobials against non-replicating persistent mycobacteria. Mycobacterium tuberculosis, the causative agent of tuberculosis, is responsible for dramatic health problems globally. It is estimated that this pathogen infects one-third of the human population and causes three million deaths annually. Most individuals remain asymptomatic for several years before developing an active disease. In such individuals, the bacilli are not cleared but rather persist in a dormant state. Major goals of TB research are to (i) understand how the bacilli remain alive for years within infected individuals, and (ii) find how to prevent their reactivation and hence clinical disease. During dormancy, most of the bacilli are confined to granulomas that consist of well-defined aggregates of different host immune cells. Granulomas prevent spreading of bacilli. In this study, we analyzed the role of a particular cell population found within granulomas, the “foamy macrophages”. These cells are filled with droplets of lipids, a well-known nutrient for persistent bacilli. We found that within these cells, the bacilli do not replicate, but remain alive and seem to internalize host lipids. The foamy macrophages might thus constitute a reservoir for persisting bacilli within their human host, and could provide a relevant model for screening of new antimicrobials against non-replicating persistent mycobacteria.