Patatin‐like phospholipases in microbial infections with emerging roles in fatty acid metabolism and immune regulation by Apicomplexa

Abstract

Summary Emerging lipidomic technologies have enabled researchers to dissect the complex roles of phospholipases in lipid metabolism, cellular signaling and immune regulation. Host phospholipase products are involved in stimulating and resolving the inflammatory response to pathogens. While many pathogen‐derived phospholipases also manipulate the immune response, they have recently been shown to be involved in lipid remodeling and scavenging during replication. Animal and plant hosts as well as many pathogens contain a family of patatin‐like phospholipases, which have been shown to have phospholipase A2 activity. Proteins containing patatin‐like phospholipase domains have been identified in protozoan parasites within the Apicomplexa phylum. These parasites are the causative agents of some of the most widespread human diseases. Malaria, caused by Plasmodium spp., kills nearly half a million people worldwide each year. Toxoplasma and Cryptosporidium infect millions of people each year with lethal consequences in immunocompromised populations. Parasite‐derived patatin‐like phospholipases are likely effective drug targets and progress in the tools available to the Apicomplexan field will allow for a closer look at the interplay of lipid metabolism and immune regulation during host infection.

Pathogens MenTORing Macrophages and Dendritic Cells: Manipulation of mTOR and Cellular Metabolism to Promote Immune Escape

“…In the context of immune responses these organelles play several important roles: they help control infection by serving as a docking site for IFN-induced proteins, they are a source of immune modulatory PUFAs such as prostaglandins E 2 (PGE 2 ), and of fatty acids that can be used to fuel Oxphos, and they play a role in cross-presentation [103]. LDs in the host are formed rapidly in response to various infectious agents following PRR signaling [104][105][106]. Given their role in aiding cross-presentation and IFN-signaling, their formation is thought to contribute to the host defense particularly in the context of viral infection [107][108][109].…”

A patatin-like phospholipase is crucial for gametocyte induction in the malaria parasite Plasmodium falciparum

“…Mammalian PNPLAs, in contrast, are mostly used in lipid metabolism and turnover, e.g. the triglyceride synthesis and lipolysis (reviewed in Wilson and Knoll, 2018). Noteworthy, PNPLAs can also be found in prokaryotic microbes like Legionella pneumophila.…”

A patatin‐like phospholipase functions during gametocyte induction in the malaria parasite Plasmodium falciparum

“…All PNPLAs exhibit a catalytic Ser-Asp dyad with the serine residue being embedded within the conserved penta-peptide Gly-Xaa-Ser-Xaa-Gly (GXSXG; reviewed in Arpigny & Jaeger, 1999; Banerji & Flieger, 2004;Ramanadham et al, 2015). Via their phospholipase A 2 (PLA 2 ) activity, PNPLAs are able to generate lysophospholipids and fatty acids, including polyunsaturated fatty acids, which are either further processed within the lipid metabolism pathway or which may act as signalling molecules (Lévêque et al, 2017;reviewed in Kienesberger et al, 2009;Ramanadham et al, 2015;Wilson & Knoll, 2018).…”

“…Lipidomics indicated partially increased levels of phospholipids and particularly measured higher absolute PC levels in the absence of PNPLA1. The lipidomics analysis was performed using four biological replicates of each line synthesis and lipolysis (reviewed inWilson & Knoll, 2018). In consequence, the loss of PLA 2 activity would evidently result in an accumulation of PC, PE and PS, and could also lead to an increased conversion of PC into SM (Figure 6).…”

“…LBPA, lysobisphosphatidic acid; LPI, lysophosphatidylinositol; PC, phosphatidylcholine; PE, phosphatidylethanolamine; PG, phosphatidylglycerol; PI, phosphatidylinositol; PL, phospholipid; PS, phosphatidylserine; SM, sphingomyelin. The lipidomics analysis was performed using four biological replicates of each line synthesis and lipolysis (reviewed inWilson & Knoll, 2018). Noteworthy, PNPLAs can also be found in prokaryotic microbes like Legionella pneumophila.…”