# Modulation of Host Lipid Pathways by Pathogenic Intracellular Bacteria
## 2 Intracellular Bacteria That Replicate Inside a Vacuole during Infection
### Host Lipids Provide Structural Integrity to Pathogen-Associated Membranes
chaffeensis_ (Figure 1). Both _A. phagocytosis_ and _E. chaffeensis_ lack the lipid-A protective layer and traditional lipopolysaccharide structures seen in most Gram-negative bacterial outer membranes. Therefore, it is likely that the addition of host cholesterol within the bacterial cell membrane is important in providing rigidity and protection that these bacteria otherwise lack during intracellular infection [50; 53]. Recently, _E. chaffeensis_ was also shown to encode a partial glycerophospholipid pathway indicating a potential requirement of host glycerophospholipids and intermediates for the production of various membrane lipids. This requirement for host membrane intermediates is supported by the finding that _E. chaffeensis_ replication in monocytic THP-1 cells is diminished when host de novo fatty acid synthesis and subsequent phospholipid production is inhibited [49]. The process of sequestering host lipids for _E. chaffeensis_ membrane construction is thought to be initiated by a type IV secretion system (T4 SS) bacterial effector protein(s), as lipid acquisition is perturbed when bacterial protein synthesis and T4 SS secretion is inhibited [49]. Conversely, _C. burnetii_ promotes phagolysosome maturation, during macrophage infection, to form an acidic parasitophorous vacuole that contains an abundance of host cholesterol and other sterols in the PCV membrane [54]. Though _C. burnetii_ infection does not require cholesterol specifically for successful infection, the regulation of the overall sterol composition within the parasitophorous vacuole is necessary for the regulation of infection stages and growth of the PCV [55]. More recent studies indicate that the sterol composition in this PCV is important for regulation of the v-ATPase pump required to maintain optimum acidity within the _Coriella_-containing vacuole. Specifically, this study showed a correlation of an increase in host cholesterol within the PCV membrane and increases in PCV acidity during later stages of mouse embryonic fibroblast _C. burnetii_ infection [56; 57] (Figure 1). Inhibition of bacterial protein synthesis followed by a decrease in sterol recruitment suggests that host sterol composition within the PCV is actively regulated by _Coriella_ effector proteins, which likely modulate endosomal trafficking and cholesterol acquisition [58; 59]. _C. burnetii_ also contains an active sterol reductase, which catalyzes the last step in the cholesterol biosynthesis pathway, implying a possible use of host sterol intermediates for bacterial completion of cholesterol production [60]. Unlike other intracellular pathogens such as _Chlamydia_ spp., _E. chaffeensis_, and _A. phagocytosis_, the use of host cholesterol or lipids for _C. burnetii_ membrane production is undefined. The presence of complete bacterial fatty acid and phospholipid biosynthesis pathways within the _C. burnetii_ genome suggests that host phospholipid incorporation may not be required for replication. Nevertheless, as described for _C. trachomatis_, host lipid incorporation in bacterial membranes may be coupled with endogenous bacterial membrane production pathways for improved intracellular replication [60]. Several studies support the requirement of host lipids for the structural integrity of obligate intracellular pathogens discussed above; however, the requirement of host lipids for de novo membrane synthesis in facultative intracellular bacterial species is not well defined. Genetically, facultative intracellular pathogens contain a higher number of complete biosynthesis pathways overall compared to obligate intracellular bacteria, and the ability to survive and replicate extracellularly indicates a lower reliance on the host for required nutrients [61; 62]. However, facultative intracellular _Salmonella_ spp. infect macrophages and reside within undeveloped phagosomes that contains host cholesterol thought to be acquired during entry, which plays a role in early vacuolar trafficking [63].