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Updated: May 21, 2026
Macrophage Cholesterol Depletion and Its Effect on the Phagocytosis of Cryptococcus neoformans
Published on: December 19, 2014
Macrophage autophagy in immunity to Cryptococcus neoformans and Candida albicans
André Moraes Nicola1, Patrícia Albuquerque, Luis R Martinez
1Departments of Microbiology and Immunology and Medicine, Albert Einstein College of Medicine, Bronx, New York, USA.
Abstract:
Autophagy is used by eukaryotes in bulk cellular material recycling and in immunity to intracellular pathogens. We evaluated the role of macrophage autophagy in the response to Cryptococcus neoformans and Candida albicans, two important opportunistic fungal pathogens. The autophagosome marker LC3 (microtubule-associated protein 1 light chain 3 alpha) was present in most macrophage vacuoles containing C. albicans. In contrast, LC3 was found in only a few vacuoles containing C. neoformans previously opsonized with antibody but never after complement-mediated phagocytosis. Disruption of host autophagy in vitro by RNA interference against ATG5 (autophagy-related 5) decreased the phagocytosis of C. albicans and the fungistatic activity of J774.16 macrophage-like cells against both fungi, independent of the opsonin used. ATG5-knockout bone marrow-derived macrophages (BMMs) also had decreased fungistatic activity against C. neoformans when activated. In contrast, nonactivated ATG5-knockout BMMs actually restricted C. neoformans growth more efficiently, suggesting that macrophage autophagy plays different roles against C. neoformans, depending on the macrophage type and activation. Interference with autophagy in J774.16 cells also decreased nonlytic exocytosis of C. neoformans, increased interleukin-6 secretion, and decreased gamma interferon-induced protein 10 secretion. Mice with a conditionally knocked out ATG5 gene in myeloid cells showed increased susceptibility to intravenous C. albicans infection. In contrast, these mice manifested no increased susceptibility to C. neoformans, as measured by survival, but had fewer alternatively activated macrophages and less inflammation in the lungs after intratracheal infection than control mice. These results demonstrate the complex roles of macrophage autophagy in restricting intracellular parasitism by fungi and reveal connections with nonlytic exocytosis, humoral immunity, and cytokine signaling.
Insights
Macrophage autophagy plays a complex role in fighting fungal infections like Candida albicans and Cryptococcus neoformans, impacting cellular immunity and inflammation.
Area of Science:
- Immunology
- Cell Biology
- Microbiology
Background:
- Autophagy is a crucial cellular process for recycling and immunity against pathogens.
- Macrophage autophagy's specific role in combating fungal infections, particularly Cryptococcus neoformans and Candida albicans, remains incompletely understood.
Purpose of the Study:
- To investigate the role of macrophage autophagy in the host response to Cryptococcus neoformans and Candida albicans.
- To elucidate the mechanisms by which autophagy influences fungal clearance, cellular activation, and immune signaling.
Main Methods:
- Utilized autophagy markers (LC3) to track autophagosome formation in macrophages infected with fungi.
- Employed RNA interference and knockout models (ATG5) in macrophage cell lines and primary bone marrow-derived macrophages (BMMs).
- Assessed fungal burden, fungistatic activity, cytokine secretion (IL-6, IP-10), and nonlytic exocytosis.
- Investigated host response in mice with conditional knockout of ATG5 in myeloid cells.
Main Results:
- Autophagy marker LC3 was associated with Candida albicans but rarely with Cryptococcus neoformans.
- Disrupting autophagy (ATG5 knockdown/knockout) impaired fungal phagocytosis and fungistatic activity against both fungi in activated macrophages.
- Non-activated ATG5-knockout macrophages showed enhanced restriction of C. neoformans growth, indicating context-dependent roles.
- Autophagy interference altered nonlytic exocytosis, increased IL-6, and decreased IP-10 secretion.
- Mice with myeloid ATG5 knockout exhibited increased susceptibility to C. albicans but not C. neoformans infection, with altered lung inflammation.
Conclusions:
- Macrophage autophagy plays multifaceted roles in restricting fungal intracellular parasitism, varying with fungal species, macrophage activation state, and cell type.
- Autophagy influences fungal clearance through mechanisms involving nonlytic exocytosis, humoral immunity, and cytokine signaling.
- These findings highlight the complex interplay between autophagy and host defense against opportunistic fungal pathogens.
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