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J Immunol. 2015 Mar 1;194(5):2345-57. doi: 10.4049/jimmunol.1402350. Epub 2015 Feb 2.

Macrophage mitochondrial and stress response to ingestion of Cryptococcus neoformans.

Author information

1
Department 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;
2
Cell Biology Department, Biology Science Institute, University of Brasilia, Brasilia CEP 70910-900, Brazil;
3
Department of Microbiology and Immunology, Albert Einstein College of Medicine of Yeshiva University, Bronx, NY 10461;
4
Department of Microbiology and Immunology, Albert Einstein College of Medicine of Yeshiva University, Bronx, NY 10461; MD Program, Albert Einstein College of Medicine of Yeshiva University, Bronx, NY 10461;
5
Department of Biology, University of Puerto Rico, Río Piedras Campus, San Juan, Puerto Rico 00931; and Undergraduate Research Program, Albert Einstein College of Medicine of Yeshiva University, Bronx, NY 10461.
6
Centre for Neuroscience and Cell Biology, University of Coimbra, 3004-504 Coimbra, Portugal; Faculty of Medicine, University of Coimbra, 3004-504 Coimbra, Portugal;
7
Department of Microbiology and Immunology, Albert Einstein College of Medicine of Yeshiva University, Bronx, NY 10461; arturo.casadevall@einstein.yu.edu.

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.

PMID:
25646306
PMCID:
PMC4340727
DOI:
10.4049/jimmunol.1402350
[Indexed for MEDLINE]
Free PMC Article

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