Modulation of Host Lipid Pathways by Pathogenic Intracellular Bacteria

Abstract

Lipids are a broad group of molecules required for cell maintenance and homeostasis. Various intracellular pathogens have developed mechanisms of modulating and sequestering host lipid processes for a large array of functions for both bacterial and host cell survival. Among the host cell lipid functions that intracellular bacteria exploit for infection are the modulation of host plasma membrane microdomains (lipid rafts) required for efficient bacterial entry; the recruitment of specific lipids for membrane integrity of intracellular vacuoles; and the utilization of host lipid droplets for the regulation of immune responses and for energy production through fatty acid β-oxidation and oxidative phosphorylation. The majority of published studies on the utilization of these host lipid pathways during infection have focused on intracellular bacterial pathogens that reside within a vacuole during infection and, thus, have vastly different requirements for host lipid metabolites when compared to those intracellular pathogens that are released into the host cytosol upon infection. Here we summarize the mechanisms by which intracellular bacteria sequester host lipid species and compare the modulation of host lipid pathways and metabolites during host cell infection by intracellular pathogens residing in either a vacuole or within the cytosol of infected mammalian cells. This review will also highlight common and unique host pathways necessary for intracellular bacterial growth that could potentially be targeted for therapeutic intervention.

Keywords: fatty acids; intracellular pathogen; lipids; β-oxidation.

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 β-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 α (PPARα); peroxisome proliferation activation receptor ɣ (PPARɣ); adipose triglyceride lipase (ATGL); fatty acid binding protein (FABP4); patatin-like phospholipase domain containing protein 2 (PNPLA2); transcription factor EB (TFEB); perilipin 2 (plin2).

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. Evidence suggests that host glycolysis is downregulated leaving other metabolic pathways, such as fatty acid β-oxidation (FAO), as likely candidates for carbon source generation required for oxidative phosphorylation and ATP production. Early studies also suggest the alteration and incorporation of host phosphatidylcholine into the rickettsial membrane, thus indicating a likely requirement of host lipid pathways for bacterial membrane structure during infection. Red arrows indicate speculated host processes and functions of host metabolites during cytosolic infection. Blue figures and words indicate known alterations that occur during infection. Black arrows indicate common pathways and functions of host metabolites. The legend on the right-hand side of the model shows a representative image of the structures use to describe Rickettsia utilization of host lipids within infected host cells.