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Macrophage Cholesterol Depletion and Its Effect on the Phagocytosis of Cryptococcus neoformans
Published on: December 19, 2014
Macrophage mitochondrial and stress response to ingestion of Cryptococcus neoformans
Carolina Coelho1, Ana Camila Oliveira Souza2, Lorena da Silveira Derengowski2
1Department of Microbiology and Immunology, Albert Einstein College of Medicine of Yeshiva University, Bronx, NY 10461; Centre for Neuroscience and Cell Biology, University of Coimbra, 3004-504 Coimbra, Portugal; Faculty of Medicine, University of Coimbra, 3004-504 Coimbra, Portugal;
Abstract:
Human infection with Cryptococcus neoformans, a common fungal pathogen, follows deposition of yeast spores in the lung alveoli. The subsequent host-pathogen interaction can result in eradication, latency, or extrapulmonary dissemination. Successful control of C. neoformans infection is dependent on host macrophages, but macrophages display little ability to kill C. neoformans in vitro. Recently, we reported that ingestion of C. neoformans by mouse macrophages induces early cell cycle progression followed by mitotic arrest, an event that almost certainly reflects host cell damage. The goal of the present work was to understand macrophage pathways affected by C. neoformans toxicity. Infection of macrophages by C. neoformans was associated with alterations in protein translation rate and activation of several stress pathways, such as hypoxia-inducing factor-1-α, receptor-interacting protein 1, and apoptosis-inducing factor. Concomitantly we observed mitochondrial depolarization in infected macrophages, an observation that was replicated in vivo. We also observed differences in the stress pathways activated, depending on macrophage cell type, consistent with the nonspecific nature of C. neoformans virulence known to infect phylogenetically distant hosts. Our results indicate that C. neoformans infection impairs multiple host cellular functions and undermines the health of these critical phagocytic cells, which can potentially interfere with their ability to clear this fungal pathogen.
Insights
Cryptococcus neoformans infection damages host macrophages, impairing their ability to clear the fungal pathogen. This study reveals how the fungus disrupts macrophage cellular functions and activates stress pathways.
Area of Science:
- Mycology
- Immunology
- Cell Biology
Background:
- Cryptococcus neoformans is a fungal pathogen that infects humans, primarily through inhalation of yeast spores.
- Host macrophages are crucial for controlling C. neoformans infections, but their in vitro killing capacity is limited.
- Previous work showed C. neoformans ingestion causes macrophage cell cycle arrest, indicating host cell damage.
Purpose of the Study:
- To investigate the specific macrophage pathways affected by C. neoformans toxicity.
- To understand the cellular mechanisms underlying C. neoformans-induced damage to host immune cells.
Main Methods:
- Infection of mouse macrophages with C. neoformans.
- Analysis of protein translation rates and stress pathway activation (hypoxia-inducing factor-1-α, receptor-interacting protein 1, apoptosis-inducing factor).
- Assessment of mitochondrial membrane potential in infected macrophages, both in vitro and in vivo.
Main Results:
- C. neoformans infection altered macrophage protein translation rates and activated multiple stress response pathways.
- Mitochondrial depolarization was observed in infected macrophages, both in vitro and in vivo.
- Differences in activated stress pathways were noted across macrophage types, reflecting C. neoformans' broad host range.
Conclusions:
- C. neoformans infection significantly impairs critical host macrophage functions.
- The fungus disrupts cellular processes and activates stress responses, potentially hindering the host's ability to eliminate the pathogen.
- Understanding these host-pathogen interactions is vital for developing effective treatments against cryptococcosis.
