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Macrophage Cholesterol Depletion and Its Effect on the Phagocytosis of Cryptococcus neoformans
Published on: December 19, 2014
Cryptococcal lipid metabolism: phospholipase B1 is implicated in transcellular metabolism of macrophage-derived
Lesley C Wright1, Rosemary M Santangelo, Ranjini Ganendren
1Centre for Infectious Diseases and Microbiology, Level 3, ICPMR Building, Westmead Hospital, Westmead NSW 2145, Australia. lesleyw@icpmr.wsahs.nsw.gov.au
Abstract:
Cryptococci survive and replicate within macrophages and can use exogenous arachidonic acid for the production of eicosanoids. Phospholipase B1 (PLB1) has a putative, but uninvestigated, role in these processes. We have shown that uptake and esterification of radiolabeled arachidonic, palmitic, and oleic acids by the Cryptococcus neoformans var. grubii H99 wild-type strain and its PLB1 deletion mutant strain (the Deltaplb1 strain) are independent of PLB1, except under hyperosmolar stress. Similarly, PLB1 was required for metabolism of 1-palmitoyl lysophosphatidylcholine (LysoPC), which is toxic to eukaryotic cell membranes, under hyperosmolar conditions. During both logarithmic and stationary phases of growth, the physiologically relevant phospholipids, dipalmitoyl phosphatidylcholine (DPPC) and dioleoyl phosphatidylcholine, were taken up and metabolized via PLB1. Exogenous DPPC did not enhance growth in the presence of glucose as a carbon source but could support it for at least 24 h in glucose-free medium. Detoxification of LysoPC by reacylation occurred in both the H99 wild-type and the Deltaplb1 strains in the presence of glucose, but PLB1 was required when LysoPC was the sole carbon source. This indicates that both energy-independent (via PLB1) and energy-dependent transacylation pathways are active in cryptococci. Phospholipase A(1) activity was identified by PLB1-independent degradation of 1-palmitoyl-2-arachidonoyl phosphatidylcholine, but the arachidonoyl LysoPC formed was not detoxified by reacylation. Using the human macrophage-like cell line THP-1, we demonstrated the PLB1-dependent incorporation of macrophage-derived arachidonic acid into cryptococcal lipids during cryptococcus-phagocyte interaction. This pool of arachidonate can be sequestered for eicosanoid production by the fungus and/or suppression of host phagocytic activity, thus diminishing the immune response.
Insights
Phospholipase B1 (PLB1) is crucial for Cryptococcus neoformans to utilize macrophage-derived arachidonic acid. This fungal enzyme aids in lipid metabolism and immune evasion, impacting host-pathogen interactions.
Area of Science:
- Mycology
- Molecular Biology
- Immunology
Background:
- Cryptococcus neoformans survives within macrophages, utilizing host lipids like arachidonic acid for eicosanoid production.
- Phospholipase B1 (PLB1) is a potential but uninvestigated enzyme involved in Cryptococcus lipid metabolism and host interaction.
Purpose of the Study:
- To investigate the role of Phospholipase B1 (PLB1) in Cryptococcus neoformans lipid metabolism, including the uptake and esterification of exogenous fatty acids and phospholipids.
- To determine PLB1's function in the detoxification of lysophosphatidylcholine (LysoPC) and its contribution to cryptococcal-macrophage interactions.
Main Methods:
- Utilized radiolabeled fatty acids and phospholipids to assess uptake and esterification in wild-type and Deltaplb1 strains of Cryptococcus neoformans var. grubii H99.
- Investigated the metabolism of 1-palmitoyl lysophosphatidylcholine (LysoPC) and dipalmitoyl phosphatidylcholine (DPPC) under various conditions, including hyperosmolar stress and different carbon sources.
- Co-cultured Cryptococcus neoformans with the human macrophage-like cell line THP-1 to examine PLB1-dependent incorporation of macrophage-derived arachidonic acid.
Main Results:
- PLB1-independent uptake and esterification of fatty acids, except under hyperosmolar stress.
- PLB1 is essential for lysophosphatidylcholine (LysoPC) metabolism and detoxification, particularly when LysoPC is the sole carbon source.
- Demonstrated PLB1-dependent incorporation of macrophage arachidonic acid into fungal lipids during host-pathogen interaction, suggesting a role in immune evasion.
Conclusions:
- Phospholipase B1 (PLB1) plays a significant role in Cryptococcus neoformans lipid metabolism, including the utilization of host-derived fatty acids.
- PLB1 is critical for detoxification pathways and nutrient acquisition, contributing to fungal survival and replication within macrophages.
- The PLB1-mediated incorporation of arachidonic acid has implications for fungal eicosanoid production and suppression of host immune responses.
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