title: Rab14 regulates maturation of macrophage phagosomes containing the fungal pathogen Candida albicans and outcome of the host-pathogen interaction.
abstract: Avoidance of innate immune defense is an important mechanism contributing to the pathogenicity of microorganisms. The fungal pathogen Candida albicans undergoes morphogenetic switching from the yeast to the filamentous hyphal form following phagocytosis by macrophages, facilitating its escape from the phagosome, which can result in host cell lysis. We show that the intracellular host trafficking GTPase Rab14 plays an important role in protecting macrophages from lysis mediated by C. albicans hyphae. Live-cell imaging of macrophages expressing green fluorescent protein (GFP)-tagged Rab14 or dominant negative Rab14, or with small interfering RNA (siRNA)-mediated knockdown of Rab14, revealed the temporal dynamics of this protein and its influence on the maturation of macrophage phagosomes following the engulfment of C. albicans cells. Phagosomes containing live C. albicans cells became transiently Rab14 positive within 2 min following engulfment. The duration of Rab14 retention on phagosomes was prolonged for hyphal cargo and was directly proportional to hyphal length. Interference with endogenous Rab14 did not affect the migration of macrophages toward C. albicans cells, the rate of engulfment, the overall uptake of fungal cells, or early phagosome processing. However, Rab14 depletion delayed the acquisition of the late phagosome maturation markers LAMP1 and lysosomal cathepsin, indicating delayed formation of a fully bioactive lysosome. This was associated with a significant increase in the level of macrophage killing by C. albicans. Therefore, Rab14 activity promotes phagosome maturation during C. albicans infection but is dysregulated on the phagosome in the presence of the invasive hyphal form, which favors fungal survival and escape.
authors: Aberdeen Fungal Group, University of Aberdeen, Aberdeen, United Kingdom.
authors: Blessing
authors: B
authors: Okai
authors: Aberdeen Fungal Group, University of Aberdeen, Aberdeen, United Kingdom.
authors: Natalie
authors: N
authors: Lyall
authors: Aberdeen Fungal Group, University of Aberdeen, Aberdeen, United Kingdom.
authors: Neil A R
authors: NA
authors: Gow
authors: Aberdeen Fungal Group, University of Aberdeen, Aberdeen, United Kingdom jude.bain@abdn.ac.uk.
authors: Judith M
authors: JM
authors: Bain
authors: Aberdeen Fungal Group, University of Aberdeen, Aberdeen, United Kingdom.
authors: Lars-Peter
authors: LP
authors: Erwig
mesh_terms: D000818:Animals; D001854:Bone Marrow Cells; D002176:Candida albicans / Q000276:immunology* / Q000472:pathogenicity; D002403:Cathepsins / Q000096:biosynthesis; D002460:Cell Line; D049452:Green Fluorescent Proteins / Q000235:genetics; D054884:Host-Pathogen Interactions / Q000276:immunology; D025301:Hyphae / Q000276:immunology*; D057131:Immune Evasion; D052118:Lysosomal-Associated Membrane Protein 1 / Q000096:biosynthesis; D008247:Lysosomes / Q000276:immunology / Q000382:microbiology; D008264:Macrophages / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D010587:Phagocytosis / Q000276:immunology*; D010588:Phagosomes / Q000235:genetics / Q000276:immunology / Q000382:microbiology; D034622:RNA Interference; D034741:RNA, Small Interfering; D020691:rab GTP-Binding Proteins / Q000235:genetics / Q000276:immunology*; D020696:rab5 GTP-Binding Proteins / Q000276:immunology; D000090802:rab7 GTP-Binding Proteins
chemical_list: D052118:Lysosomal-Associated Membrane Protein 1; D034741:RNA, Small Interfering; D000090802:rab7 GTP-Binding Proteins; D049452:Green Fluorescent Proteins; D002403:Cathepsins; C555882:Rab14 protein, mouse; D020691:rab GTP-Binding Proteins; D020696:rab5 GTP-Binding Proteins
references: Small GTPases. 2013 Jul-Sep;4(3):148-58
references: 24088602
references: MBio. 2013;4(6):e00810-13
references: 24169578
references: Cell Microbiol. 2014 Jul;16(7):1034-52
references: 24373249
references: J Cell Biol. 2001 Jan 8;152(1):165-80
references: 11149929
references: EMBO J. 2001 Feb 15;20(4):683-93
references: 11179213
references: Int J Med Microbiol. 2002 Feb;291(6-7):487-94
references: 11890548
references: J Cell Sci. 2002 Sep 15;115(Pt 18):3703-13
references: 12186956
references: Biochem J. 2002 Sep 15;366(Pt 3):689-704
references: 12061891
references: Infect Immun. 2002 Nov;70(11):6319-29
references: 12379711
references: Trends Cell Biol. 2003 Mar;13(3):137-45
references: 12628346
references: Mol Cell Biol. 2003 Sep;23(18):6494-506
references: 12944476
references: J Clin Microbiol. 2004 Apr;42(4):1519-27
references: 15070998
references: Mol Biol Cell. 2004 May;15(5):2218-29
references: 15004230
references: Clin Infect Dis. 2004 Aug 1;39(3):309-17
references: 15306996
references: J Bacteriol. 1966 Mar;91(3):1346-55
references: 4956335
references: Parasitology. 1981 Aug;83(Pt 1):115-23
references: 6267544
references: Am J Vet Res. 1985 Feb;46(2):332-5
references: 3922258
references: Infect Immun. 1991 Sep;59(9):3291-6
references: 1879943
references: J Exp Med. 1993 Jun 1;177(6):1605-11
references: 8496679
references: Int J Biochem Cell Biol. 1997 May;29(5):715-20
references: 9251238
references: Cell. 1997 Sep 5;90(5):939-49
references: 9298905
references: J Cell Sci. 1999 Oct;112 ( Pt 19):3237-48
references: 10504329
references: Cell Microbiol. 2005 Jun;7(6):765-78
references: 15888080
references: Traffic. 2005 Aug;6(8):635-53
references: 15998320
references: Cell. 2005 Sep 9;122(5):735-49
references: 16143105
references: FEBS Lett. 2006 Oct 2;580(22):5241-6
references: 16962593
references: Expert Opin Biol Ther. 2006 Sep;6(9):891-903
references: 16918256
references: MBio. 2014;5(6):e01874
references: 25467440
references: EMBO J. 2006 Nov 15;25(22):5250-9
references: 17082769
references: Proc Natl Acad Sci U S A. 2007 Nov 20;104(47):18520-5
references: 18006660
references: Nature. 2007 Nov 29;450(7170):725-30
references: 18046412
references: Microbiol Mol Biol Rev. 2007 Dec;71(4):636-52
references: 18063721
references: J Cell Biol. 2008 Jan 28;180(2):357-73
references: 18227280
references: Proc Natl Acad Sci U S A. 2008 Nov 4;105(44):16952-7
references: 18971338
references: Cell Microbiol. 2009 Apr;11(4):560-89
references: 19134116
references: Infect Immun. 2009 Apr;77(4):1596-605
references: 19188358
references: Nat Rev Microbiol. 2009 May;7(5):355-66
references: 19369951
references: Nat Rev Mol Cell Biol. 2009 Aug;10(8):513-25
references: 19603039
references: Science. 2009 Sep 4;325(5945):1250-4
references: 19729655
references: Infect Immun. 2010 Apr;78(4):1650-8
references: 20123707
references: Proc Natl Acad Sci U S A. 2010 Oct 19;107(42):18016-21
references: 20921409
references: PLoS One. 2010;5(11):e14084
references: 21124879
references: Analyst. 2011 Sep 7;136(17):3527-33
references: 21283889
references: J Immunol. 2011 Sep 15;187(6):3072-86
references: 21849684
references: PLoS One. 2011;6(10):e26626
references: 22039519
references: PLoS Pathog. 2012;8(3):e1002578
references: 22438806
references: Trends Immunol. 2012 Aug;33(8):397-405
references: 22560866
references: PLoS One. 2012;7(7):e39858
references: 22911692
references: PLoS One. 2013;8(7):e68668
references: 23844232
references: Cell Microbiol. 2014 Feb;16(2):296-310
references: 24119134