Lipid droplets and lipid mediators in viral infection and immunity

Abstract

Lipid droplets (LDs) contribute to key pathways important for the physiology and pathophysiology of cells. In a homeostatic view, LDs regulate the storage of neutral lipids, protein sequestration, removal of toxic lipids and cellular communication; however, recent advancements in the field show these organelles as essential for various cellular stress response mechanisms, including inflammation and immunity, with LDs acting as hubs that integrate metabolic and inflammatory processes. The accumulation of LDs has become a hallmark of infection, and is often thought to be virally driven; however, recent evidence is pointing to a role for the upregulation of LDs in the production of a successful immune response to viral infection. The fatty acids housed in LDs are also gaining interest due to the role that these lipid species play during viral infection, and their link to the synthesis of bioactive lipid mediators that have been found to have a very complex role in viral infection. This review explores the role of LDs and their subsequent lipid mediators during viral infections and poses a paradigm shift in thinking in the field, whereby LDs may play pivotal roles in protecting the host against viral infection.

Keywords: antiviral; immunity; infection; lipid droplets; lipid mediators; virus.

Figure 1.

Homeostatic LD biogenesis from the endoplasmic reticulum (ER), and LD biogenesis from pathogen infection. Homeostatic LD synthesis can occur following three crucial steps. Neutral lipids are synthesized in the ER where these neutral lipids begin to aggregate. When neutral lipid synthesis reaches a threshold, LD budding toward the cytosol occurs forming the beginning of a tethered LD. The tethered LD continues to accumulate neutral lipids resulting in expansion of the LD until a fission-like mechanism results in the detachment of the nascent LD into the cytoplasm. LDs are also induced upon infection with pathogens by the activation of either Toll-like receptors or epidermal growth factor receptor (EGFR).

Figure 2.

Lipid droplets are sites for lipid mediator synthesis. Polyunsaturated fatty acids (PUFAs; mainly from TGs) such as arachidonic acid can be sequestered into LDs where they can undergo synthesis within the COX/LOX pathway. This synthesis yields bioactive lipid mediators such as prostaglandins, leukotrienes and lipoxins. Sphingosine-1-phosphate (S1P) has been demonstrated to interact with LDs through the promotion of ceramide synthesis and storage as well as platelet-activating factor (PAF), which has been demonstrated to promote LPS- and sepsis-induced LD formation.

Figure 3.

Lipid mediators in viral infection. Lipid mediators can act in both a prohost and proviral sense during infection. Lipid mediators [prostaglandin E₂ (PGE₂), dimethyl prostaglandin A1 (dmPGA1), leukotriene B4 (LTB4), sphingosine-1-phosphate (S1P), platelet-activating factor (PAF) and lysophosphatidic acid (LPA)] all act to either restrict or foster viral replication. Lipid mediators can also act in a proviral manner to increase the production of inflammatory cytokines, restrict type-1 IFN signaling and increase cell–cell fusion [resolvin E1(RvE1), protectin D1 (PD1) and lipoxins]. On the other hand, lipid mediators can decrease inflammatory cytokines and promote macrophage differentiation.