title: Cryptococcus strains with different pathogenic potentials have diverse protein secretomes.
abstract: Secreted proteins are the frontline between the host and pathogen. In mammalian hosts, secreted proteins enable invasive infection and can modulate the host immune response. Cryptococcosis, caused by pathogenic Cryptococcus species, begins when inhaled infectious propagules establish to produce pulmonary infection, which, if not resolved, can disseminate to the central nervous system to cause meningoencephalitis. Strains of Cryptococcus species differ in their capacity to cause disease, and the mechanisms underlying this are not well understood. To investigate the role of secreted proteins in disease, we determined the secretome for three genome strains of Cryptococcus species, including a hypovirulent and a hypervirulent strain of C. gattii and a virulent strain of C. neoformans. Sixty-seven unique proteins were identified, with different numbers and types of proteins secreted by each strain. The secretomes of the virulent strains were largely limited to proteolytic and hydrolytic enzymes, while the hypovirulent strain had a diverse secretome, including non-conventionally secreted canonical cytosolic and immunogenic proteins that have been implicated in virulence. The hypovirulent strain cannot establish pulmonary infection in a mouse model, but strains of this genotype have caused human meningitis. To directly test brain infection, we used intracranial inoculation and found that the hypovirulent strain was substantially more invasive than its hypervirulent counterpart. We suggest that immunogenic proteins secreted by this strain invoke a host response that limits pulmonary infection but that there can be invasive growth and damage if infection reaches the brain. Given their known role in virulence, it is possible that non-conventionally secreted proteins mediate this process.
authors.affiliation: School of Molecular Bioscience, University of Sydney, Sydney, NSW, Australia.
authors.forename: Leona T
authors.initials: LT
authors.lastname: Campbell
authors.affiliation: School of Molecular Bioscience, University of Sydney, Sydney, NSW, Australia.
authors.forename: Anna R
authors.initials: AR
authors.lastname: Simonin
authors.affiliation: School of Molecular Bioscience, University of Sydney, Sydney, NSW, Australia.
authors.forename: Cuilan
authors.initials: C
authors.lastname: Chen
authors.affiliation: School of Molecular Bioscience, University of Sydney, Sydney, NSW, Australia.
authors.forename: Jannatul
authors.initials: J
authors.lastname: Ferdous
authors.affiliation: ithree Institute, University of Technology, Sydney, NSW, Australia.
authors.forename: Matthew P
authors.initials: MP
authors.lastname: Padula
authors.affiliation: ithree Institute, University of Technology, Sydney, NSW, Australia.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Harry
authors.affiliation: School of Molecular Bioscience, University of Sydney, Sydney, NSW, Australia.
authors.forename: Markus
authors.initials: M
authors.lastname: Hofer
authors.affiliation: School of Molecular Bioscience, University of Sydney, Sydney, NSW, Australia.
authors.forename: Iain L
authors.initials: IL
authors.lastname: Campbell
authors.affiliation: School of Molecular Bioscience, University of Sydney, Sydney, NSW, Australia dee.carter@sydney.edu.au.
authors.forename: Dee A
authors.initials: DA
authors.lastname: Carter
mesh_terms: D000818:Animals; D003455:Cryptococcus neoformans / Q000235:genetics / Q000378:metabolism / Q000472:pathogenicity*; D005656:Fungal Proteins / Q000235:genetics / Q000378:metabolism*; D016919:Meningitis, Cryptococcal / Q000382:microbiology*; D051379:Mice; D010447:Peptide Hydrolases / Q000235:genetics / Q000378:metabolism; D055571:Secretory Pathway; D014774:Virulence / Q000235:genetics
chemical_list: D005656:Fungal Proteins; D010447:Peptide Hydrolases
references.citation: FEMS Yeast Res. 2007 Jun;7(4):499-510
references.pmid: 17233760
references.citation: Database (Oxford). 2011;2011:bar001
references.pmid: 21300622
references.citation: World J Biol Chem. 2010 May 26;1(5):160-80
references.pmid: 21541001
references.citation: Nucleic Acids Res. 2015 Jan;43(Database issue):D213-21
references.pmid: 25428371
references.citation: J Exp Med. 2008 Sep 29;205(10):2319-37
references.pmid: 18779347
references.citation: Eukaryot Cell. 2008 Jan;7(1):58-67
references.pmid: 18039940
references.citation: Trends Genet. 2003 Aug;19(8):415-7
references.pmid: 12902157
references.citation: Eukaryot Cell. 2007 Jan;6(1):48-59
references.pmid: 17114598
references.citation: Protein Eng Des Sel. 2004 Apr;17(4):349-56
references.pmid: 15115854
references.citation: Proteomics. 2007 Sep;7(17):3171-83
references.pmid: 17676664
references.citation: FEMS Yeast Res. 2006 Jun;6(4):645-51
references.pmid: 16696661
references.citation: Mol Microbiol. 2006 Nov;62(4):970-83
references.pmid: 17038119
references.citation: Mol Biosyst. 2009 Apr;5(4):345-50
references.pmid: 19396370
references.citation: J Cell Sci. 2012 Nov 15;125(Pt 22):5251-5
references.pmid: 23377655
references.citation: Acta Trop. 2013 Oct;128(1):116-23
references.pmid: 23850506
references.citation: Am J Pathol. 2013 Oct;183(4):1144-55
references.pmid: 23911657
references.citation: J Proteome Res. 2010 Aug 6;9(8):3832-41
references.pmid: 20545298
references.citation: Trends Biochem Sci. 1999 Jan;24(1):8-11
references.pmid: 10087914
references.citation: Annu Rev Microbiol. 2006;60:69-105
references.pmid: 16704346
references.citation: Infect Immun. 1997 Jul;65(7):2599-605
references.pmid: 9199426
references.citation: IUBMB Life. 2011 Jul;63(7):457-62
references.pmid: 21491559
references.citation: J Food Prot. 2001 Mar;64(3):401-4
references.pmid: 11252488
references.citation: PLoS One. 2009;4(6):e5780
references.pmid: 19492051
references.citation: Emerg Infect Dis. 2010 Feb;16(2):251-7
references.pmid: 20113555
references.citation: Microbiology. 1997 Feb;143 ( Pt 2):313-20
references.pmid: 9043108
references.citation: PLoS One. 2014;9(7):e103488
references.pmid: 25075521
references.citation: PLoS Pathog. 2010 Apr;6(4):e1000850
references.pmid: 20421942
references.citation: Microbiology. 2008 Nov;154(Pt 11):3266-80
references.pmid: 18957581
references.citation: Int J Biochem Cell Biol. 2007;39(6):1190-203
references.pmid: 17449317
references.citation: Emerg Infect Dis. 2010 Jan;16(1):14-20
references.pmid: 20031037
references.citation: J Biomed Biotechnol. 2012;2012:156795
references.pmid: 23118496
references.citation: Infect Immun. 2010 Apr;78(4):1601-9
references.pmid: 20145096
references.citation: IUBMB Life. 2011 Jul;63(7):489-94
references.pmid: 21698752
references.citation: J Antimicrob Chemother. 2012 Jun;67(6):1432-8
references.pmid: 22378683
references.citation: Med Mycol. 2001 Dec;39(6):495-507
references.pmid: 11798055
references.citation: Infect Immun. 2009 Jul;77(7):2703-11
references.pmid: 19380472
references.citation: Cell Host Microbe. 2013 May 15;13(5):521-34
references.pmid: 23684304
references.citation: Autophagy. 2010 Jul;6(5):650-1
references.pmid: 20473033
references.citation: Microbiology. 2012 Jan;158(Pt 1):240-58
references.pmid: 21998162
references.citation: Mol Biochem Parasitol. 2014 Feb;193(2):75-81
references.pmid: 24602601
references.citation: J Med Microbiol. 2003 Aug;52(Pt 8):615-22
references.pmid: 12867553
references.citation: Nucleic Acids Res. 2013 Jan;41(Database issue):D43-7
references.pmid: 23161681
references.citation: J Bacteriol. 1997 Aug;179(16):4992-9
references.pmid: 9260938
references.citation: Electrophoresis. 1999 Dec;20(18):3551-67
references.pmid: 10612281
references.citation: J Cell Biol. 2010 Feb 22;188(4):527-36
references.pmid: 20156967
references.citation: PLoS One. 2012;7(11):e48570
references.pmid: 23144903
references.citation: Microbiol Mol Biol Rev. 2003 Sep;67(3):400-28, table of contents
references.pmid: 12966142
references.citation: Mol Biol Cell. 1999 May;10(5):1463-75
references.pmid: 10233156
references.citation: Immunity. 2001 Nov;15(5):825-35
references.pmid: 11728343
references.citation: Proteomics. 2009 May;9(9):2578-88
references.pmid: 19343717
references.citation: Appl Microbiol Biotechnol. 2008 Sep;80(3):381-8
references.pmid: 18636256
references.citation: Int Arch Allergy Immunol. 1998 May;116(1):29-35
references.pmid: 9623506
references.citation: J Virol. 2012 Jun;86(12):6932-46
references.pmid: 22496215
references.citation: Parasite Immunol. 2013 Dec;35(12):457-67
references.pmid: 23927077
references.citation: Int Arch Allergy Immunol. 2002 Mar;127(3):181-90
references.pmid: 11979043
references.citation: Proteomics. 2010 Feb;10(4):799-827
references.pmid: 19953550
references.citation: Proteomics. 2013 Feb;13(3-4):597-608
references.pmid: 23349114
references.citation: Emerg Infect Dis. 2011 Feb;17(2):193-9
references.pmid: 21291588
references.citation: Clin Exp Allergy. 2011 May;41(5):739-49
references.pmid: 21488999