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

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.

Towards understanding the functional diversity of cell wall mycolic acids of Mycobacterium tuberculosis

“…Foamy macrophages containing multiple cholesterol loaded lipid bodies constitute a distinct trait of tuberculous granulomas and a safe haven for mycobacteria, since they have been found to harbor multiple bacilli [150,151]. Induction by mycolic acids of macrophages rich in lipid bodies was further confirmed on human monocyte-derived macrophages [152]. Here, the authors further showed that oxygenated mycolic acids, mostly of the keto class, play a leading role in the observed foamy macrophage formation.…”

Dormant Mycobacterium tuberculosis Fails To Block Phagosome Maturation and Shows Unexpected Capacity To Stimulate Specific Human T Lymphocytes

“…It may be thought that R-Mtb shifts to dormancy within infected macrophages after having subverted their antimicrobial and APC potential (11). Additionally, M. tuberculosis may reside within subverted or foamy macrophages in mature granulomas (51,52), where T cells are physically separated from infected cells by a fibrous wall or caseum that limits APC/lymphocyte interactions (4). Lastly, M. tuberculosis may rest dormant in non-APC, representing sites of immunoprivilege (14) for M. tuberculosis persistence in LTBI.…”

The Pathology ofMycobacterium tuberculosisInfection

“…2b, arrows) predominate in advanced TB and are only induced by virulent mycobacteria in response to oxygenated mycolic acids. 165 These cells are thought to provide a nutrient-rich, protective reservoir for Mtb persistence, as these cells have reduced microbicidal and phagocytic activity. Foamy macrophages can also induce apoptosis of Th1 cells through the Fas/Fas ligand mechanism while suppressing their own apoptosis through high expression of the antiapoptotic Bcl2 molecule.…”