# 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
These bacterial and host modifications provide PC species with an increased branch number, making these sequestered lipids similar to typical bacteria-made membrane lipids suitable for the production of bacterial progeny [24; 38; 39; 40; 41]. _C. trachomatis_ also encodes phosphatidylserine decarboxylase and acyl-ACP synthase enzymes supporting the notion that these bacteria have the ability to modify and utilize host lipids during infection [42; 43]. Although _C. trachomatis_ is able to modify host PCs, this bacteria is also able to produce other phospholipid species utilizing the bacterial type II fatty acid synthesis (FASII) pathway, which when combined with host lipid modification of scavenged lipids, allows for efficient reproduction during intracellular infection [44]. _Anaplasma phagocytosisoptimilum_ and _Ehrlichia chaffeensis_ are closely related bacterial species that halt the phagosome-lysosome fusion step of the endocytic pathway and reside within a non-acidic, early and late endosome, respectively, during intracellular infection [45; 46]. During mammalian infection, _A. phagocytosisoptimilum_ targets neutrophils, and _E. chaffensis_ predominantly infects monocytes [46]. Similar to _C. trachomatis, A. phagocytosisoptimilum_ and _E. chaffensis_, require cholesterol for persistence but do not genetically encode for anabolic cholesterol pathways; thus, cholesterol present within bacterial compartments is captured from the host [47; 48]. Similar to _C. trachomatis_ PCVs, _A. phagocytosisoptimilum_ PCVs contain cholesterol-rich domains to enable microtubule trafficking for nutrient-rich endosome fusion, though the specific protein:protein interactions involved have yet to be elucidated [49]. However, unlike _Chlamydia_ spp., _A. phagocytosisoptimilum_ infection of HL-60 promyeloblasts does not require host de novo cholesterol synthesis and, instead, actively stimulates uptake of lipoproteins by the host cell and recruitment to the PCV through regulation of the Niemann-Pick disease type C1 (NPC1)-mediated intracellular cholesterol trafficking [50; 51; 52]. The mechanism for sequestering cholesterol from the host  
Figure 1: Mechanisms for acquisition and utilization of host lipids by intracellular pathogens. Intracellular pathogens that reside within a vacuole utilize host lipids for various processes during infection. This model depicts the host lipid pathways and methods exploited by various vacuolar bacterial species to enhance intracellular and, ultimately, mammalian infection. The approaches employed by these pathogenic bacteria include (i) lipid acquisition into pathogen-associated membranes as seen in _Ehrlichia, Anaplasma, Chlamydia,_ and _Coxiella_ (from left to right); (ii) pathogen- and host-stimulated lipid droplet modulation required during _Chlamydia, Coxiella, Mycobacterium,_ and _Salmonella_ infection (from left to right); (iii) immune modulation and lipid inflammatory mediator production from lipid droplets seen during _Chlamydia, Coxiella,_ and _Mycobacterium_ infection (from left to right); (iv) acquirement of host fatty acid \(\beta\)-oxidation (FAO) metabolites for energy production by _Mycobacterium_ and modulation of host FAO regulators by _Chlamydia_; (v) regulation of bacterial stage transition of _Legionella_ initiated by host intracellular lipid composition. The legend on the bottom left-hand side of the model shows a representative image of the structures used in the panels describing each pathogens’ utilization of host lipids. Toll-like receptor 2 (TLR2); NOD-like receptor protein 3 (NLRP3); peroxisome proliferation activation receptor \(\alpha\) (PPAR\(\alpha\)); peroxisome proliferation activation receptor Y (PPAR Y); adipose triglyceride lipase (ATGL); fatty acid binding protein (FABP4); patatin-like phospholipase domain containing protein 2 (PNPLA2); transcription factor EB (TFEB); perilipin 2 (_plin2_). cell during _E. chaffeensis_ infection is not well defined; however, host cholesterol is incorporated into the bacterial membranes of both _A. phagocytophilium_ and _E.