Lipid Droplet, a Key Player in Host-Parasite Interactions

Abstract

Lipid droplets (lipid bodies, LDs) are dynamic organelles that have important roles in regulating lipid metabolism, energy homeostasis, cell signaling, membrane trafficking, and inflammation. LD biogenesis, composition, and functions are highly regulated and may vary according to the stimuli, cell type, activation state, and inflammatory environment. Increased cytoplasmic LDs are frequently observed in leukocytes and other cells in a number of infectious diseases. Accumulating evidence reveals LDs participation in fundamental mechanisms of host-pathogen interactions, including cell signaling and immunity. LDs are sources of eicosanoid production, and may participate in different aspects of innate signaling and antigen presentation. In addition, intracellular pathogens evolved mechanisms to subvert host metabolism and may use host LDs, as ways of immune evasion and nutrients source. Here, we review mechanisms of LDs biogenesis and their contributions to the infection progress, and discuss the latest discoveries on mechanisms and pathways involving LDs roles as regulators of the immune response to protozoan infection.

Keywords: eicosanoids; immune response; inflammation; intracellular pathogen; lipid bodies; lipid droplets; parasite.

Figure 1

Lipid droplets (LDs) on parasites lipid homeostasis. Trypanosoma spp., Leishmania spp., Plasmodium spp., and Toxoplasma gondii cannot synthesize cholesterol, and the energy and lipid source for them is the host lipid synthesis and host LDs, as well as low-density lipoproteins, eventually high-density lipoproteins particles and lipoprotein lipase. The close relationship with other organelles through Rab proteins can be lipid sources, such as endoplasmic reticulum (ER) for sterol and Golgi complex (GC) for sphingolipid sources. Although the mechanisms are still unknown, some parasites can store lipids on their LD. Lipoprotein- and ABC-proteins are involved in the mammalian lipid transport, as well as important enzymes to lipid synthesis like ACAT and DGAT proteins. These proteins are also present in T. gondii and ACAT-like proteins are present in Trypanosoma cruzi. The parasite transfer lipids to their own LD to be stored, but in Plasmodium spp., or they metabolize them as in Plasmodium and T. gondii. The parasite and host LDs are involved in essential cell functions that can favor the survival of the parasite, such as energy and lipid source for intracellular parasites proliferation. They also can isolate lipids or toxic metabolites from the cytoplasm for detoxification, such as hemozoin from heme on Plasmodium-infected cell LD.

Figure 2

Host cell lipid droplet (LD) biogenesis in response to interaction with protozoan parasites. Increased numbers of LDs occur in the cytoplasm of many cell types after infection with different parasite-containing vesicles as well as on cytoplasm of these parasites, such as Trypanosoma spp., Leishmania spp., Plasmodium spp., and Toxoplasma gondii. The signaling from toll-like receptors (TLRs) by pathogens and pathogen-derived molecules triggers signaling pathways, such as PPARs and MAPKs, which are involved in the formation of LD. LDs produce lipid mediators; they compartmentalize both the substrate and the enzymatic machinery necessary for eicosanoid syntheses, such as cPLA2, cyclooxygenases (COX)-2, and prostaglandin synthases. Prostaglandin E₂ (PGE₂) production benefits parasite survival, as shown in Trypanosoma, Leishmania, Plasmodium, and Toxoplasma infections. On the other hand, leukotriene B₄ (LTB₄) production by host cells via P2 × 7 receptor is related to parasite killing as seen in Leishmania infection, where LDs biogenesis and an anti-inflammatory balance in the PGE₂/LTB₄ axis could facilitate the Leishmania transmissibility and infection in vivo. Cytoplasmic LD in Leishmania express prostaglandin F2α synthase (PGFS) responsible for PGF_2α production. The PGF_2α receptor (FP) is present on parasite vacuole (PV) surface, suggesting these LDs could act as a virulence factor. Then, LD could be involved in inflammation and immune evasion.

Figure 3

Lipid droplets (LDs) and the molecular mechanisms regulating immune response during protozoan infection. Interferon (IFN)-γ receptor signaling induces transduction of GTPases family molecules—immunity-related GTPases (GKS e IRGM proteins) and GPBs subfamilies—that play essential roles in membrane vesicular trafficking, autophagy, and antimicrobial and anti-inflammatory responses. IRGM are abundant proteins on LDs and “protects self-vesicles” from GKS and guanylate binding proteins (GBPs) destruction by autophagy machinery. The inactive GKS and GBP proteins built a pool of molecules available on cytoplasm and could have a stable association with the IRGM-deficient membrane, as parasitophorous vacuole membrane and eventually as LDs, to target them to autophagy, or lipophagy, respectively. LDs provide fatty acids, and lipids employed the phagophore membrane, implying their enzymes [steryl esters (STEs) and TAGs] on autophagosome biogenesis. IFN-γ signaling induces upregulation of LDs, and it appears to involve perilipin 2 (PLIN2)/ADRP that physically associates with IRGM. LD is also related to cross-presentation pathway since depletion of LDs by pharmacological inhibition of DGAT and by PLIN2/ADRP deficiency led to decreased LD biogenesis and cross-presentation since MHC-I surface expression, and the rate of antigen-presenting cell conjugated with T CD8+ lymphocyte are reduced.