Mycobacteria and the Greasy Macrophage: Getting Fat and Frustrated

Abstract

In the current issue of Infection and Immunity, Caire-Brändli and coworkers (Infect. Immun. 82:476 -490, 2014, doi:10.1128 /IAI.01196-13) describe a novel cell system for studying mycobacterial interactions with foamy macrophages and provide a magnificent series of electron microscopy-based observations providing major insight into the microbiology and cell biology of these interactions. With nearly 9 million new cases and 1.3 million deaths each year, as indicated by the World Health Organization (WHO) in its 2013 global report (1), tuberculosis (TB) remains a leading cause of mortality due to a single bacterial pathogen, namely Mycobacterium tuberculosis. The development of new tools for controlling, and possibly even eradicating TB, such as new antimicrobial drugs, a more effective vaccine than Mycobacterium bovis BCG, and innovative host-targeted strategies (2), is hampered primarily by the incomplete nature of our understanding of the molecular and cellular aspects of host-pathogen interactions in TB.Pulmonary macrophages are the primary host cells for the TB bacillus (3, 4). M. tuberculosis thrives in these cells during the first few weeks of infection, until adaptive immunity kicks in, helping the body to control the proliferation of the pathogen through cytokine-mediated macrophage activation and other mechanisms (5). The continued recruitment of T and B lymphocytes to the site of infection and the concomitant death of infected macrophages leads to the formation of a complex structure with a well-organized architecture, the granuloma, a hallmark of TB (6-8). M. tuberculosis can persist for decades within the granuloma, in a dormant state referred to as "latency." It has been estimated that up to 2 billion individuals may carry such latent infection and that the disease will reactivate in about 10% of these individuals, at some point in their lifetime.One of the most striking features of the TB granuloma is the presence around the lesion of a specific population of histiocytes/ macrophages enriched in lipid droplets (LD) and known as foamy macrophages (9, 10). Foamy macrophages have been observed in a number of inflammatory conditions, including infectious and noninfectious diseases, such as natural and experimental TB in particular (11-16). M. tuberculosis slows its multiplication rate in foamy macrophages and accumulates LD in its own cytoplasm. It has been suggested that foamy macrophages (i) constitute a reservoir of nutrients for the pathogen during latency, supplying carbon and energy, in particular, via various lipids, including triacylglycerol (TAG) (9, 10), and (ii) participate in the formation of the caseous center of the granuloma after the death of the macrophages, releasing their lipid content (10,17). The mechanisms by which mycobacteria induce foam cell differentiation and by which LD accumulate in the bacterial cytoplasm within infected cells remain interesting areas of investigation. In particular, the way in which the intracellular mycobacterial vacuole, or phagosome, interacts with the ...

MAB_3551c encodes the primary triacylglycerol synthase involved in lipid accumulation in Mycobacterium abscessus

“…Notably, at least seven genes encoding putative Tgs are present in the M. abscessus genome, suggesting that M. abscessus, like M. tuberculosis, is capable of producing TAG. Production and accumulation of TAG in the form of ILI by tuberculous mycobacteria is a hallmark feature of the bacilli that persist during latent tuberculosis and it is believed that the lipids within these ILI represent a source of energy and carbon during latent infection and reactivation of the disease (Low et al, 2009;Kapoor et al, 2013;Caire-Br€ andli et al, 2014;Neyrolles, 2014). Residing within specialized lipid-rich tissues or cells, rather than in conventional macrophages, would be beneficial for M. tuberculosis persistence within granulomatous lesions.…”

Delineating the Physiological Roles of the PE and Catalytic Domains of LipY in Lipid Consumption in Mycobacterium-Infected Foamy Macrophages

“…In the present study, the experimental model system of very-low-density lipoprotein (VLDL)-driven FM (7) was used to delineate the physiological role of the PE domain of LipY in the hydrolysis of both host-derived TAG and mycobacterial TAG within ILI. Reasons for choosing this model system have been described in detail elsewhere (7,12,14,29). After internalization of VLDL by receptor-mediated endocytosis, the neutral lipids of this lipoprotein will undergo hydrolysis in lysosomes (Ly).…”

Hijacking and Use of Host Lipids by Intracellular Pathogens

“…This dysregulation enables feedback activation of the antilipolytic G protein–coupled receptor GPR109A, leading to perturbations in lipid homeostasis and consequent accumulation of lipid bodies in the macrophage (202). Other mycobacterial molecules have been shown to be involved in the accumulation of lipid in foamy cells, including lipoarabinomannan, mycolic acids and ESAT-6, a secreted virulence factor (203). …”