**1. Introduction**

*M. tuberculosis* and *M. leprae* are intracellular pathogens. *M. tuberculosis* can survive up to decades in a phenotypically non-replicating dormant state, primarily in hypoxic granulomas in the lung [1]. The otherwise drug-susceptible dormant mycobacteria show the remarkable property to develop drug resistance within the granulomas of the host. These nonreplicative drug-resistant bacteria within the host´s tissues are called persisters [2].

Mycobacteria have outstanding mechanisms to escape from elimination and have a high degree of intrinsic resistance to most antibiotics, chemotherapeutic agents and immune eradication [3,4]. One major obstacle for host defence mechanisms and therapeutic interven‐ tion is the robust, mycolic acid-rich cell wall, which is unique among prokaryotes [3,5]. In the last years it has become apparent that mycobacteria induce the accumulation of lipids in the host cells and use them as energy and carbon source. This strategy is regarded as another crucial factor for the long term-survival of *M. tuberculosis* and *M. leprae* in the host. Most mycobacteria have the ability to synthesize lipid bodies as reservoirs for fatty acids. The lipid droplet- containing macrophages are called "foamy macrophages" and are the hallmark of *M. tuberculosis* and *M. leprae* infection.

*M. leprae* is the causative agent of leprosy. Leprosy is a chronic infectious disease caused by the obligate intracellular bacterium *Mycobacterium leprae* and is a major source of morbidity in developing countries [6,7]. Leprosy patients show two major manifestations of the disease, known as as lepromatous leprosy (LL), and tuberculoid leprosy (TT) [6]. TT is observed in patients with good T-cell mediated (Th1) immunity and is characterized by granuloma formation and death of Schwann cells (Scs) leading to myelin degradation and nerve destruc‐ tion [8,9]. Patients with poor T-cell mediated immunity show the lepromatous type leprosy (LL), which leads to a high bacterial load inside host cells specially in Schwann cells and macrophages [8,10-12]. For both forms of leprosy damage of the nerves is observed [12].

© 2013 Stehr et al.; licensee InTech. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2013 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Lepromatous leprosy lesions of the skin, eyes, nerves, and lymph nodes are characterized by tumor-like accumulations of foamy macrophages. The foamy macrophages are fully packed with lipid droplets (LDs) and contain high numbers of leprosy bacilli. These aggregations of foamy macrophages expand slowly and disfigure the body of the host [13].

ferase, (WS/DGAT) synthesizes TAG for lipid body formation. WS/DGAT is an integral membrane protein and synthesizes a growing globule around the cytoplasmic portion of the enzyme. Finally the lipid body is released to the cytoplasm. The origin of the surface phos‐

Lipid Inclusions in Mycobacterial Infections http://dx.doi.org/10.5772/54526 33

The accumulation of lipid droplets occurs also in several infectious, and inflammatory conditions, including in atherosclerosis [25], bacterial sepsis [26], viral infections [27], and in mycobacterial infections [15,28,29]. *M. tuberculosis* infected macrophages store mostly neutral lipids, while cells infected with *M. leprae* seem to accumulate next to TAG a high degree of

LDs are observed in various cells of the immune system including macrophages, neutrophils, and eosinophils. The structure and composition of LDs is highly conserved. They contain a core of neutral lipid esters typically TAG, but also sterols and sterol esters [31-36]. The surface is covered by a phospholipid monolayer, which is composed at least in some cells by unique

*M. leprae* infects preferentially macrophages and Schwann cells [11]. A typical feature of lepromatous leprosy is the survival and replication of. *M. leprae* within the lipid droplets stored in the enlarged phagosome of histiocytes. Lipid droplets are thought to be an important nutrient source for the bacillus. A major concern in leprosy is peripheral neuropathy. The damage to nerves of the peripheral nervous system is caused by the the infection of Schwann cells (SCs) by *M. leprae*. In LL nerve biopsies, highly infected SCs also contain lipid droplets and show a foamy appearance, such as Virchow cells found in dermal lesions [38]. The biology of the these foamy cells has been characterized poorly until now. Neither the origin or nature of the lipids has been elucidated yet. Only recently it *in vitro* studies by Mattos could show that ML induces the formation of lipid droplets in human SCs [10]. Moreover, the group found that LDs are promptly recruited to bacterial phagosomes. In SCs LD recruiting by bacterial phagosomes depends on cytoskeletal reorganization and PI3K signaling, but is independent

Important markers for the lipid accumulation in adipocytes or macrophages are lipid-dropletassociated proteins such as adipose differentiation-related protein ADRP and perilipin, which play essential roles in lipid-droplet formation [39]. After phagocytosis of live *M. leprae* ADRP expression is constantly upregulated in human monocytes. ADRP and perilipin are localized

Prokaryotes do not generally produce lipid bodies containing TAG. Accumulation of TAG in intracellular lipid-bodies is mostly restricted to bacteria belonging to the actinomycetes

Most mycobacterial species accumulate considerable amounts of TAG during infection [24,41-44]. The intracellular pathogen *M. tuberculosis* can survive up to decades in a pheno‐

pholipid monolayer is not known [22,24].

cholesterol and cholesterol esters [10,30].

**2.1. Lipid droplets in the host**

of TLR2 bacterial sensing [10].

**2.2. Lipid bodies in the pathogen**

group [40].

at the phagosomal membrane (Figure 4) [39].

fatty acids [37].

The finding that *M. leprae* has insufficient fatty acid synthetase activity to support growth lead to the hypothesis that *M. leprae* scavenges lipids from the host cell [14]. Over the last years it has become evident that survival and persistence of *M. tuberculosis* is critically dependent on lipid body formation. Furthermore lipid body formation seems to be the prerequisite for transition of *M. tuberculosis* to the dormant state. The formation of foamy macrophages is a process which appears to be a key event in both sustaining persistent bacteria and release of infectious bacilli [15]. This goes along with the important observation that sputum from tuberculosis patients contains lipid body-laden bacilli [16,17].

In the dormant state lipids from lipid bodies appear to be the primary carbon source for *M. tuberculosis* in vivo. For *M. tuberculosis* several bacterial genes are upregulated during the dormant state and have been reported to be involved in lipid metabolism such as diacylglycerol acyltransferase (tgs1), lipase (lipY), and isocitrate lyase (icl) [18,19].

*M. leprae* has a small genome (3.2 Mb). The obligate intracellular organism shows a moderate genome degradation and several genes are absent when compared with other mycobacterial species. Due to the gene loss *M. leprae* is strongly dependent on the host for basic metabolic functions [8,20]. Macrophages infected with *M. leprae* contain oxidized host lipids and it has been observed that *M. leprae* upregulates 13 host lipid metabolism genes in T-lep lesions and 26 in L-lep lesions. The oxidized lipids inhibit innate immune responses and thus seem to be an important virulence factor for the organism [21].

This review highlights the importance of the LDs as one of the most unique determinant for persistence and virulence of *M. tuberculosis* and *M. leprae*. The formation of LDs in *M. tubercu‐ losis and M. leprae* in infected host cells shall be compared and the lipid metabolism of both organisms will be discussed.

In this review we will use the term "lipid droplets" for lipid-rich inclusions in the host and "lipid bodies" for lipid-rich inclusions in the pathogen.
