# Modulation of Host Lipid Pathways by Pathogenic Intracellular Bacteria
## 2 Intracellular Bacteria That Replicate Inside a Vacuole during Infection
### Fatty Acid \(\beta\)-Oxidation for Energy Production  
The ability of bacterial pathogens to generate energy is required for survival and replication during infection of a mammalian host. There are a well-known and characterized range of biosynthesis pathways, both host and bacterial, that have the potential to be employed for energy production. A wide range of bacteria utilize glucose, or a sugar carbon source derivative, as a quick energy source. Glucose is most efficiently used through glycolysis followed by cellular respiration or other aerobic processes [115]. However, glucose and other sugars are not the only carbon sources available and utilized for energy production. Lipids as a carbon source provide more energy per molecule and can be processed through fatty acid \(\beta\)-oxidation (FAO), a pathway found in both microbes and eukaryotes, to produce acetyl-CoA for use in cellular respiration [115; 116]. Generally, extracellular bacteria depend less on host processes and encode for the energy pathways necessary for efficient survival, growth, and disease progression. In contrast, intracellular bacteria rely more heavily on nutrients provided by host biosynthesis processes for efficient infection and growth. As mentioned previously, facultative intracellular bacteria typically have functional pathways that allow these organisms to survive and replicate in both extracellular and intracellular environments, whereas obligate intracellular pathogens rely heavily on host metabolites during infection [61; 62]. For example, _M. tuberculosis_ employs multiple mechanisms to sequester host lipids as a carbon source. This facultative intracellular bacteria encodes phospholipases, such as phospholipase C, to breakdown host lipids before employment of bacterial mammalian cell entry (Mce) protein transporter complexes and homologs of flavin adenine dinucleotide (Fad) transporter protein to import cholesterol and fatty acids into the bacterial cell [117; 118; 119]. Cholesterol and fatty acids are the primary carbon source used for _M. tuberculosis_'s production of energy, making host lipid production important for sustainable and efficient infection [119; 120; 121; 122]. Interestingly, _M. tuberculosis_ also encodes for 200 distinct enzymes used for lipid metabolism that are involved in shuttling and processing degraded fatty acids during in vivo infection [123; 124; 107; 125]. There are two main pathways utilized by _M. tuberculosis_ for bacterial lipid catabolism, i.e., FAO and the glycoxylate shunt, with the latter being the dominant pathway. Interestingly, the _M. tuberculosis_ genome has a large amount of redundancy regarding predicted enzymes within the FAO pathway to predominantly catabolize lipids into acetyl-CoA, which is then shuttled to the tricarboxylic acid cycle (TCA) indicating a potential significance of this secondary pathway during infection [126; 127] (Figure 1). The utilization of various lipids as an energy source and the redundancy of lipid metabolic pathways allow _M. tuberculosis_ to have enhanced plasticity and adaptability and to persist during long-term mammalian infection [128]. It is important to note that because of the plasticity of _M. tuberculosis_ metabolism, cholesterol is not required for active _M. tuberculosis_ infection. Nevertheless, the use of cholesterol as a major carbon source is necessary for increased persistence during chronic infections [129]. Although _M. tuberculosis_ is able to self-process exogenous cholesterol and lipids as a carbon source through bacterial FAO, a recent study indicates a requirement of active host FAO during infection. Host FAO is important for regulation of antibacterial responses such as reactive oxygen species production and phagosome acidification. _M. tuberculosis_, therefore, is thought to stimulate FAO during infection to promote downregulation of these bactericidal responses [130]. Interestingly, the obligate intracellular bacteria, _Chlamydia_ spp.