# Modulation of Host Lipid Pathways by Pathogenic Intracellular Bacteria
## 3 Intracellular Bacteria That Replicate within the Cytosol
### Fatty Acid \(\beta\)-Oxidation for Energy Production  
As described for intracellular pathogens that reside inside a vacuole, energy metabolism is an essential factor involved in the maintenance and sustainability of active infection. Due to the genomic decay and increased reliance on host processes and the importance of energy for efficient intracellular pathogen infection, much research has been done to elucidate the host energy pathways required during infection. Although there is an increased reliance on the host metabolism during intracellular infection, some pathogens still contain energy pathways necessary for self-sustainable energy production. One of the major energy-producing pathways is FAO, which catabolizes lipids, either acquired from exogenous lipids, de novo lipids, or lipid storages, for acetyl-CoA generation and use in host or bacterial OXPHOS. It is important to note that when comparing energy metabolism between vacuolar and cytosolic intracellular pathogens, the nutrients within the cellular compartments are vastly different. For example, vacuolar bacteria have adapted to utilize a diverse range of metabolites that are recruited and associated with PCVs during infection. In contrast, cytosolic bacteria do not employ this strategy and are limited to using available metabolites within the cytosol for energy production. A study of host metabolites present during _L. monocytogenes_ infection of _Drosophila melanogaster_, for example, showed an overall downregulation in energy metabolites, such as triglycerides, glycogen storages, and other intermediates required for the major energy pathways, FAO and glycolysis. This downregulated shift in metabolism is speculated to be an antibacterial response to prevent bacterial use of energy stores or to be a bacterial mechanism employed to block antibacterial responses, such as use of major energy metabolites for regulation of reactive oxygen species used by the host cell as an antibacterial mechanism, as seen with _M. tuberculosis_[130; 160]. Similar to _Mycobacterium_ spp. variation in virulent potential, _Rickettsia_ spp. also vary in their capacity to cause disease in mammals. A recent study demonstrated that a recognized human pathogen, _R. conorii_, is able to invade into and efficiently replicate within both non-phagocytic and phagocytic mammalian cells. In contrast, _Rickettsia montanensis_, a species that is not recognized as pathogenic to mammals, can proliferate in epithelial cells but is rapidly killed intracellularly in macrophage-like THP-1 cells. This study suggested that growth within professional phagocytic cells may be a key determinant to distinguish pathogenic _Rickettsia_ spp. from non-pathogenic species [161]. In addition, a proteomic study revealed the differential host protein changes that occur when macrophage-like THP-1 cells are infected with either _R. conorii_ or _R. montanensis_. In the _R. conorii_ infected cells, host glycolysis and other sugar metabolic processes were downregulated while proteins involved in OXPHOS were upregulated. In contrast, infection with _R. montanensis_ did not result in these changes. The observed overall increase in OXPHOS and decrease in glycolysis during _R. conorii_ infection of macrophages, strongly suggested that non-sugar carbon sources, such as lipids, are likely important for energy production. This proteomic analysis also indicated a shift in host lipid metabolic pathways and a requirement of the anabolic FASN, discussed previously, for de novo production of host lipids (Figure 2). These metabolic shifts are also not observed during _R. montanensis_ infection of macrophages. Taken together, these results suggest that the ability to stimulate specific host metabolic pathways within macrophages and possibly other target cells likely contributes to the virulence potential of _R. conorii_ and related pathogenic spotted fever group _Rickettsia_ species [159]. Similar to _R. conorii_, the closely related cytosolic bacteria _O.