title: Investigation of the function of Candida albicans Als3 by heterologous expression in Candida glabrata.
abstract: During hematogenously disseminated infection, blood-borne Candida albicans invades the endothelial cell lining of the vasculature to invade the deep tissues. Although the C. albicans Als3 invasin is critical for invasion and damage of endothelial cells in vitro, a C. albicans als3Δ/Δ mutant has normal virulence in the mouse model of disseminated infection. We hypothesized that the contribution of Als3 to virulence is obscured by the presence of additional C. albicans invasins. To elucidate the in vivo function of Als3, we heterologously expressed C. albicans ALS3 in Candida glabrata, a yeast that lacks a close ALS3 ortholog and has low virulence in mice. We found that following intravenous inoculation into mice, the ALS3-expressing strain preferentially trafficked to the brain, where it induced significantly elevated levels of myeloperoxidase, tumor necrosis factor, monocyte chemoattractant protein 1, and gamma interferon. Also, the ALS3-expressing strain had enhanced adherence to and invasion of human brain microvascular endothelial cells in vitro, demonstrating a potential mechanism for ALS3-mediated neurotropism. In addition, upon initiation of infection, the ALS3-expressing strain had increased trafficking to the cortex of the kidneys. With prolonged infection, this strain persisted in the kidneys at significantly higher levels than the control strain but did not induce an elevated inflammatory response. Finally, the ALS3-expressing strain had increased resistance to neutrophil killing in vitro. These results indicate that during disseminated infection, Als3 mediates initial trafficking to the brain and renal cortex and contributes to fungal persistence in the kidneys.
authors: Division of Infectious Diseases, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, California, USA.
authors: Yue
authors: Y
authors: Fu
authors: Quynh T
authors: QT
authors: Phan
authors: Guanpingsheng
authors: G
authors: Luo
authors: Norma V
authors: NV
authors: Solis
authors: Yaoping
authors: Y
authors: Liu
authors: Brendan P
authors: BP
authors: Cormack
authors: John E
authors: JE
authors: Edwards
authors: Ashraf S
authors: AS
authors: Ibrahim
authors: Scott G
authors: SG
authors: Filler
mesh_terms: D000818:Animals; D001921:Brain / Q000382:microbiology / Q000473:pathology; D002176:Candida albicans / Q000235:genetics / Q000276:immunology / Q000472:pathogenicity*; D041221:Candida glabrata / Q000235:genetics / Q000378:metabolism*; D002177:Candidiasis / Q000382:microbiology; D002448:Cell Adhesion; D002460:Cell Line; D015169:Colony Count, Microbial; D004705:Endocytosis; D005656:Fungal Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D015966:Gene Expression Regulation, Fungal; D005800:Genes, Fungal; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D007249:Inflammation / Q000276:immunology / Q000378:metabolism / Q000382:microbiology; D016209:Interleukin-8 / Q000378:metabolism; D007672:Kidney Cortex / Q000382:microbiology / Q000473:pathology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009504:Neutrophils / Q000382:microbiology; D009195:Peroxidase / Q000378:metabolism; D021381:Protein Transport
chemical_list: C113620:ALS3 protein, Candida albicans; C508606:CXCL8 protein, human; D005656:Fungal Proteins; D016209:Interleukin-8; D009195:Peroxidase
references: Infect Immun. 2013 Apr;81(4):1267-76
references: 23381995
references: PLoS Biol. 2007 Mar;5(3):e64
references: 17311474
references: J Infect Dis. 2005 Jul 15;192(2):336-43
references: 15962230
references: PLoS Pathog. 2010 Mar 26;6(3):e1000827
references: 20361054
references: Infect Immun. 2010 Mar;78(3):1066-77
references: 20008535
references: Cancer. 2009 Oct 15;115(20):4745-52
references: 19634156
references: J Infect Dis. 2006 Jul 15;194(2):256-60
references: 16779733
references: J Leukoc Biol. 2005 Aug;78(2):338-44
references: 15857941
references: Arch Biochem Biophys. 1962 Mar;96:465-7
references: 13909511
references: Infect Immun. 2003 Apr;71(4):1680-8
references: 12654781
references: Am J Pathol. 2001 Mar;158(3):879-91
references: 11238037
references: Mol Microbiol. 2009 Apr;72(1):155-69
references: 19220748
references: PLoS Pathog. 2006 Jul;2(7):e63
references: 16839200
references: BMC Physiol. 2004 May 17;4:10
references: 15147582
references: Genetics. 1999 Mar;151(3):979-87
references: 10049916
references: Infect Immun. 2005 Aug;73(8):4588-95
references: 16040970
references: PLoS Pathog. 2011 Oct;7(10):e1002305
references: 21998592
references: PLoS Genet. 2005 Jul;1(1):36-57
references: 16103911
references: Mol Microbiol. 2002 Oct;46(2):479-92
references: 12406223
references: Microbiology (Reading). 2011 Jun;157(Pt 6):1806-1815
references: 21436220
references: Mol Cell Biol. 2000 Feb;20(3):971-8
references: 10629054
references: Infect Immun. 2005 Mar;73(3):1852-5
references: 15731087
references: Infect Immun. 1999 Oct;67(10):5522-5
references: 10496943
references: Int J Immunopathol Pharmacol. 2006 Jul-Sep;19(3):561-5
references: 17026841
references: Microbiology (Reading). 2005 Mar;151(Pt 3):673-681
references: 15758214
references: PLoS One. 2012;7(6):e39633
references: 22745797
references: J Clin Invest. 1973 Nov;52(11):2745-56
references: 4355998
references: Infect Immun. 2001 Aug;69(8):5046-55
references: 11447185
references: Biochim Biophys Acta. 1978 Jul 7;525(1):37-44
references: 28769
references: J Innate Immun. 2011;3(2):180-99
references: 21063074
references: Am J Physiol. 1995 Dec;269(6 Pt 1):C1417-32
references: 8572171
references: Antimicrob Agents Chemother. 1997 Sep;41(9):1937-9
references: 9303388
references: Infect Immun. 2000 Jun;68(6):3485-90
references: 10816502
references: J Biol Chem. 2005 Mar 18;280(11):10455-61
references: 15632157
references: Infect Immun. 2008 Oct;76(10):4370-7
references: 18573891
references: Infect Immun. 1995 Mar;63(3):976-83
references: 7868270
references: J Biol Chem. 2004 Jul 16;279(29):30480-9
references: 15128742
references: Eukaryot Cell. 2010 Oct;9(10):1432-40
references: 20675576
references: J Microbiol Methods. 2009 Jul;78(1):71-8
references: 19427882