# Modulation of Host Lipid Pathways by Pathogenic Intracellular Bacteria
## 3 Intracellular Bacteria That Replicate within the Cytosol
### Host Lipids Provide Structural Integrity to Bacterial Membranes  
The phospholipid and lipid membrane spp. that compose bacterial membranes are similar for most bacterial species as described previously. A distinct difference when discussing membranes associated with vacuolar pathogens and cytosolic pathogens is the presence of a PCV during vacuolar bacterial infection. As discussed previously, various host lipids are recruited to the PCV membrane to provide a variety of functions for the vacuolar bacteria. Cytosolic bacteria, however, do not remain within a vacuole; thus, the incorporation of host lipids into pathogen-associated membranes during replication is limited to the bacterial membrane. Most studies discussing the incorporation of host lipids into the cytosolic bacterial membranes focused on elucidating bacterial membrane compositions and speculated that various lipid classes originated from the infected host cell. Genomic analysis of various _Rickettsia_ spp. and another related bacterial species, _Orientia tsutsugamushi_, indicates gaps within the biosynthetic pathways necessary to construct the bacterial cell wall and membrane structure. This suggests a requirement of host lipid metabolites for membrane production during intracellular replication and growth [152; 153; 154]. A more recent genomic study denoted multiple lipid anabolic pathways that are missing or incomplete, within various rickettsial genomes, implying a large reliance on the host to provide the enzymes and intermediates necessary for full functional lipid biosynthesis pathways. Among the lipid metabolic pathways lacking or incomplete in the described _Rickettsia_ spp. are pathways involved in lipopolysaccharideacharide production and fatty acid and PC synthesis, supporting the implication that there is a heavy rickettsial reliance on host enzymes and metabolic intermediates for lipid products required for adequate building of the bacterial membrane [155]. Interestingly, previous experiments investigating the phospholipid composition of _Rickettsia prowazekii_ in chicken embryo yolk sacs indicated the presence of PC and cardiolipins, later found to compose 5.1% and 2.1% of the membrane lipid composition, respectively [156] (Figure 2). Gram-negative bacterial membranes are predominantly composed of saturated and branched fatty acid chains, with limited sterol structures [24; 25]. PC is not a normal component of the canonical Gram-negative inner or outer membrane, suggesting that the PC is likely sequestered from the host [157]. Studies have also shown that _Rickettsia rickettsii_ membranes contain a moderate amount of unsaturated lipids and that _R. prowazekii_ membranes contain cholesterol, in further support that membrane components may be actively acquired from the infected host cell [156; 158]. Recently, a proteomic study defining host alterations during _Rickettsia conorii_ infection of macrophages showed that inhibition of host fatty acid synthase (FASN), an enzyme required for lipid biosynthesis, is detrimental for bacterial replication and survival. A major role in the host cell and possible requirement of FASN for _R. conorii_ growth is the production of phospholipids for membrane production, though the function of host FASN-produced lipids is not defined [159] (Figure 2). Figure 2: Potential host lipid pathways altered during cytosolic _Rickettsia_ infection. A representative cytosolic, intracellular bacteria species, _Rickettsia conorii_, requires host fatty acid synthase, and therefore, free fatty acids for successful replication. Mammalian infection with rickettsial pathogens also alters host prostaglandin production to stimulate the presentation of disease. Metabolically, _Rickettsia_ spp. are not self-sufficient and require the host for survival; however, the host pathways required for energy production and subsequent bacterial survival are largely unknown.