Leishmania parasites possess a platelet-activating factor acetylhydrolase important for virulence

Abstract

Leishmania parasites are intracellular protozoans capable of salvaging and remodeling lipids from the host. To understand the role of lipid metabolism in Leishmania virulence, it is necessary to characterize the enzymes involved in the uptake and turnover of phospholipids. This study focuses on a putative phospholipase A2 (PLA2)/platelet-activating factor acetylhydrolase (PAF-AH) in L. major. In mammals, PAF-AH is a subgroup of PLA2 catalyzing the hydrolysis/inactivation of platelet-activating factor (PAF), a potent mediator of many leukocyte functions. By immunofluorescence microscopy, L. major PLA2/PAF-AH is predominantly localized in the ER. While wild type L. major parasites are able to hydrolyze PAF, this activity is completely absent in the PLA2/PAF-AH-null mutants. Meanwhile, deletion of PLA2/PAF-AH had no significant effect on the turnover of common glycerophospholipids such as phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine, and phosphatidylglycerol. PLA2/PAF-AH is not required for the growth of L. major parasites in culture, or the production of GPI-anchored virulence factors. Nonetheless, it does play a key role in the mammalian host as the PLA2/PAF-AH null mutants exhibit attenuated virulence in BALB/c mice. In conclusion, these data suggest that Leishmania parasites possess a functional PAF-AH and the degradation of PAF or PAF-like lipids is an important step in infection.

Platelets in the immune response: Revisiting platelet-activating factor in anaphylaxis

“…Leishmania species, an intracellular protozoan, expresses PAF-AH, which appears to play a key role in virulence of the organism. 112 It is clear that the PAF signaling pathway is fundamental to a number of pathologic processes, and therefore control of this pathway should hold great promise in the therapeutic arena. We are still in the early stages of understanding PAF signaling, and further investigation of its role in pathology and therapeutic modulation is highly anticipated.…”

Phosphatidylcholine synthesis through cholinephosphate cytidylyltransferase is dispensable in Leishmania major

“…This PE N-methylation pathway is the predominant PC synthesis route in hepatocytes 31 and Saccharomyces cerevisiae 32 , but is absent in Trypanosoma brucei 33,34 . Additionally, Leishmania can directly take up lipids including glycerophospholipids from the host or media and then remodel them into parasite-specific lipids 35–38 . So why would Leishmania parasites retain multiple, seemingly redundant PC synthesis pathways (Fig.…”

Endocytosis and Exocytosis in Leishmania amazonensis Are Modulated by Bromoenol Lactone

“…In different pathogenic microorganisms (including bacteria and protozoa) PLA 2 activity is important for the pathogen interaction with host cells (Connelly and Kierszenbaum, 1984;Saffer and Schwartzman, 1991;Silverman et al, 1992). In Leishmania, different studies showed the presence of PLA 2 activity in L. amazonensis and of a platelet-activating factor acetylhydrolase (PAF-AH) in L. major (Henriques et al, 2003;Passero et al, 2008;Pawlowic and Zhang, 2012). Unlike that reported by Passero et al (2008), we showed here that most PLA 2 activity in L. amazonensis promastigotes is present in the parasite and not in the culture supernatant (conditioned medium) (Figure 2A).…”