# Modulation of Host Lipid Pathways by Pathogenic Intracellular Bacteria
## 2 Intracellular Bacteria That Replicate Inside a Vacuole during Infection
### Host Lipid-Droplet Modulation  
Lipid droplets (LDs) are a host cellular compartments used to store predominantly neutral, esterified cholesterol and triacylglycer levels, surrounded by a phospholipids monolayer with lipid-associated proteins, which can serve various functions including energy production and immune response modulation [69; 70]. Some pathogens, such as _Chlamydia pneumoniae_, _Chlamydia trachomatis_, _Coxiella burnetii_, and _M. tuberculosis_ produce foam cells during macrophage infection, characterized by an overaccumulation of LDs within the host cell [71]. This lipid accumulation in macrophages and the subsequent alteration of metabolism and immune signaling correlate with changes in macrophage polarization, which have been shown to be important during macrophage infection by various intracellular pathogens [72; 73]. _C. pneumoniae_ and _C. trachomatis_ induce a \"foamy\" cell phenotype during macrophage infection by employing a bacterial cholesterol esterification enzyme, CT149, to form cholesterol esters that are subsequently stored in LDs [42]. During macrophage infection, _C. pneumoniae_ also actively downregulates host transcription factors, peroxisome proliferator-activated receptors (PPAR) \(\alpha\) and Y. These two proteins are both known to be involved in the regulation of LD breakdown and cholesterol efflux, providing a likely mechanism for the formation of the foam cell phenotype during infection [74; 75; 76; 77]. Immune regulation also occurs through the stimulation of the host inflammasome, NLRP3, and toll-like receptor (TLR) 2 to subsequently increase LD formation in infected macrophages. However, the function(s) or consequences of host lipid overaccumulation into LDs during infection by _C. pneumoniae_ is not yet clearly elucidated [78; 79]. Conversely, _C. trachomatis_ employs the modulation of fatty acids within host LDs for immune response regulation by recruiting host triacylglycerol lipases to the LDs associated with the bacterial PCVs. These host lipases breakdown the stored triacylglycer levels within the LDs into immune signaling intermediates, such as arachidonic acid, to be converted into immune mediators, such as prostaglandamins, for enhancement of tissue damage and overall disease during mammalian infection [40; 80]. Stimulation of lipases for prostaglandin production can be induced by pathogen infection of a single cell and by host cell-to-host cell signaling caused by the infection. Therefore, infected and uninfected bystander cells within a mammalian host are likely involved in overall prostaglandin production during infection. As described previously, lipids are also scavenged from PCV-associated LDs for bacterial membrane production [24; 38; 39; 40] (Figure 1). It is important to note that although LDs are a major source of lipids for _C. trachomatis_ during intracellular growth, these host structures are not required during mouse embryonic fibroblast infection. Interestingly, during inhibition of LD formation in mouse embryonic fibroblasts, _C. trachomatis_ is able to efficiently grow when free fatty acids are supplemented. This suggests that the bacteria are able to recruit free fatty acids and other host lipids not related to LDs to the PCV as a way of compensating for a lack of lipids within LDs [81]. Similarly, _C. burnetii_'s formation of foam cells is actively modulated by bacterial effector proteins and is dependent on an increase in fatty acid recruitment to the endoplasmic reticulum for packaging into host LDs [82]. During _C. burnetii_ infection of macrophages, the expression of host proteins involved in LD breakdown, including patatin-like phospholipase domain containing protein 2 (PNPLA2) or adipose triglyceride lipase (ATGL), acyl-CoA:cholesterol transferase, and fatty acid binding protein (FABP4), is modulated suggesting a requirement of host lipids within LDs, such as cholesterol esters and triacylglycer levels, during infection [82; 83; 84; 85].