**2.1. Lipid droplets in the host**

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

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

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

*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

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

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

The current models of lipid droplet biogenesis are still hypothetical and have been reviewed extensively by Murphy in 1999 and Ohsaki in 2009 [22,23]. The most common model supposes that the membrane protein diacyltransferase DGAT1 synthesizes triacylglycerols (TAG), which accumulate between the two membrane leaflets of the endoplasmic reticulum (ER) to be finally released by budding. The lipids are covered by a phospholipid monolayer from the

The formation of lipid bodies in bacteria has been even less characterized. Wältermann et al. suggested in 2005 that a bifunctional wax ester synthase/acyl-CoA:diacylglycerol acyltrans‐

foamy macrophages expand slowly and disfigure the body of the host [13].

tuberculosis patients contains lipid body-laden bacilli [16,17].

32 Tuberculosis - Current Issues in Diagnosis and Management

an important virulence factor for the organism [21].

"lipid bodies" for lipid-rich inclusions in the pathogen.

**2. Biogenesis of lipid inclusions in bacteria and eukaryotes**

organisms will be discussed.

ER membrane.

acyltransferase (tgs1), lipase (lipY), and isocitrate lyase (icl) [18,19].

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 cholesterol and cholesterol esters [10,30].

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 fatty acids [37].

*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 of TLR2 bacterial sensing [10].

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