title: Macrophage mitochondrial and stress response to ingestion of Cryptococcus neoformans.
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.
authors: 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;
authors: Carolina
authors: http://orcid.org/0000-0002-7523-3031
authors: C
authors: Coelho
authors: Cell Biology Department, Biology Science Institute, University of Brasilia, Brasilia CEP 70910-900, Brazil;
authors: Ana Camila Oliveira
authors: AC
authors: Souza
authors: Cell Biology Department, Biology Science Institute, University of Brasilia, Brasilia CEP 70910-900, Brazil;
authors: Lorena da Silveira
authors: Lda S
authors: Derengowski
authors: Department of Microbiology and Immunology, Albert Einstein College of Medicine of Yeshiva University, Bronx, NY 10461;
authors: Carlos
authors: C
authors: de Leon-Rodriguez
authors: 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;
authors: Bo
authors: B
authors: Wang
authors: 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.
authors: Rosiris
authors: R
authors: Leon-Rivera
authors: Cell Biology Department, Biology Science Institute, University of Brasilia, Brasilia CEP 70910-900, Brazil;
authors: Anamelia Lorenzetti
authors: AL
authors: Bocca
authors: Centre for Neuroscience and Cell Biology, University of Coimbra, 3004-504 Coimbra, Portugal; Faculty of Medicine, University of Coimbra, 3004-504 Coimbra, Portugal;
authors: Teresa
authors: T
authors: Gonçalves
authors: Department of Microbiology and Immunology, Albert Einstein College of Medicine of Yeshiva University, Bronx, NY 10461; arturo.casadevall@einstein.yu.edu.
authors: Arturo
authors: A
authors: Casadevall
mesh_terms: D000818:Animals; D051033:Apoptosis Inducing Factor / Q000235:genetics / Q000276:immunology; D002460:Cell Line; D003455:Cryptococcus neoformans / Q000276:immunology / Q000472:pathogenicity*; D020690:GTPase-Activating Proteins / Q000235:genetics / Q000276:immunology; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D054884:Host-Pathogen Interactions / Q000276:immunology*; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000276:immunology; D008264:Macrophages / Q000276:immunology* / Q000382:microbiology / Q000473:pathology; D017737:Macrophages, Peritoneal / Q000276:immunology* / Q000382:microbiology / Q000473:pathology; D053078:Membrane Potential, Mitochondrial; D051379:Mice; D008928:Mitochondria / Q000276:immunology* / Q000473:pathology; D010587:Phagocytosis; D014176:Protein Biosynthesis; D015398:Signal Transduction
chemical_list: D051033:Apoptosis Inducing Factor; D020690:GTPase-Activating Proteins; C497443:Hif1a protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; C494830:AIFM1 protein, mouse; C490620:Ralbp1 protein, mouse
references: Biochim Biophys Acta. 2011 Jul;1813(7):1263-8
references: 20732359
references: Infect Immun. 2000 Feb;68(2):832-8
references: 10639453
references: Nat Rev Microbiol. 2010 Oct;8(10):693-705
references: 20818415
references: Immunol Invest. 2011;40(7-8):692-722
references: 21592044
references: Blood. 2011 Mar 3;117(9):2625-39
references: 21148811
references: PLoS Pathog. 2012;8(3):e1002551
references: 22457616
references: J Exp Med. 1980 Oct 1;152(4):808-22
references: 6252274
references: J Clin Invest. 2011 Oct;121(10):3889-901
references: 21911939
references: J Cell Biol. 2012 Apr 2;197(1):45-57
references: 22472439
references: Blood. 2012 Aug 16;120(7):1422-31
references: 22786879
references: Infect Immun. 2009 Sep;77(9):3749-58
references: 19564388
references: Mol Microbiol. 2012 Apr;84(2):383-99
references: 22443190
references: Proc Natl Acad Sci U S A. 2009 Jan 27;106(4):1228-33
references: 19164571
references: Mol Cell Biol. 2006 Jul;26(14):5449-69
references: 16809779
references: PLoS Pathog. 2012;8(3):e1002555
references: 22396644
references: MBio. 2011;2(4). pii: e00158-11. doi: 10.1128/mBio.00158-11
references: 21828220
references: Infect Immun. 2012 Apr;80(4):1455-66
references: 22252868
references: Infect Immun. 2005 Jan;73(1):504-13
references: 15618190
references: Am J Pathol. 2011 Jan;178(1):198-211
references: 21224057
references: Infect Immun. 2007 Oct;75(10):4792-8
references: 17664261
references: Eur J Immunol. 2011 May;41(5):1196-202
references: 21469137
references: Eukaryot Cell. 2012 May;11(5):560-70
references: 22447924
references: Proc Natl Acad Sci U S A. 2002 Jun 25;99(13):8892-7
references: 12077295
references: Proc Natl Acad Sci U S A. 2013 Oct 1;110(40):16003-8
references: 24043775
references: Am J Respir Cell Mol Biol. 1994 Aug;11(2):130-7
references: 8049074
references: Infect Immun. 1999 Aug;67(8):3703-13
references: 10417127
references: MBio. 2011;2(3):e00103-11
references: 21652778
references: Proc Natl Acad Sci U S A. 2002 Mar 5;99(5):3165-70
references: 11880650
references: Infect Immun. 2000 Jul;68(7):4225-37
references: 10858240
references: Commun Integr Biol. 2010 Jul;3(4):390-1
references: 20798836
references: Antimicrob Agents Chemother. 1998 Jun;42(6):1437-46
references: 9624491
references: Sci Rep. 2013;3:1328
references: 23435464
references: Parasitol Res. 2010 Nov;107(6):1313-21
references: 20680337
references: Infect Immun. 1998 Feb;66(2):664-9
references: 9453624
references: Proc Natl Acad Sci U S A. 2011 Mar 1;108(9):3612-7
references: 21321208
references: Biotechniques. 2011 Feb;50(2):98-115
references: 21486251
references: Oncogene. 1999 Nov 1;18(45):6112-20
references: 10557102
references: Nat Rev Microbiol. 2009 Feb;7(2):99-109
references: 19148178
references: Cell Host Microbe. 2012 Jul 19;12(1):60-70
references: 22817988
references: Infect Immun. 2013 Nov;81(11):4091-9
references: 23980105
references: Cell Host Microbe. 2012 Oct 18;12(4):470-83
references: 23084916
references: Infect Immun. 2012 Apr;80(4):1467-78
references: 22252872
references: J Immunol. 2005 Sep 1;175(5):3244-51
references: 16116215
references: BMC Immunol. 2007;8:16
references: 17705844
references: Adv Appl Microbiol. 2014;87:1-41
references: 24581388
references: Virulence. 2010 May-Jun;1(3):197-201
references: 21178442
references: Annu Rev Immunol. 2002;20:795-823
references: 11861618
references: J Biol Chem. 2012 Jun 29;287(27):22838-53
references: 22589537
references: Nucleic Acids Res. 2013 Jan;41(Database issue):D808-15
references: 23203871
references: Infect Immun. 1999 Feb;67(2):885-90
references: 9916104
references: J Cell Biol. 1994 May;125(4):917-28
references: 7514607
references: Clin Exp Immunol. 1994 Nov;98(2):217-23
references: 7955525
references: Future Microbiol. 2013 Sep;8(9):1107-16
references: 24020739
references: Cancer Res. 2010 Mar 1;70(5):2010-9
references: 20179204
references: Annu Rev Immunol. 2011;29:1-21
references: 20936972
references: Nat Rev Immunol. 2003 Jan;3(1):23-35
references: 12511873
references: Infect Immun. 1983 Dec;42(3):1109-15
references: 6642661
references: J Immunol. 2005 Jun 1;174(11):7226-33
references: 15905568
references: PLoS Pathog. 2011 Jun;7(6):e1002078
references: 21698225
references: Annu Rev Pathol. 2014;9:219-38
references: 24050625
references: Proc Natl Acad Sci U S A. 2013 Aug 27;110(35):14336-41
references: 23940348
references: Infect Immun. 2011 May;79(5):1915-26
references: 21383052
references: Eukaryot Cell. 2007 Dec;6(12):2169-74
references: 17951515