Mechanisms of Trafficking to the Brain
During hematogenously disseminated disease, Candida albicans infects most organs, including the brain. We discovered that a C. albicans vps51Δ/Δ mutant had significantly increased tropism for the brain in the mouse model of disseminated disease. To investigate the mechanisms of this enhanced trafficking to the brain, we studied the interactions of wild-type C. albicans and the vps51Δ/Δ mutant with brain microvascular endothelial cells in vitro. These studies revealed that C. albicans invasion of brain endothelial cells is mediated by the fungal invasins, Als3 and Ssa1. Als3 binds to the gp96 heat shock protein, which is expressed on the surface of brain endothelial cells, but not human umbilical vein endothelial cells, whereas Ssa1 binds to a brain endothelial cell receptor other than gp96. The vps51Δ/Δ mutant has increased surface expression of Als3, which is a major cause of the increased capacity of this mutant to both invade brain endothelial cells in vitro and traffic to the brain in mice. Therefore, during disseminated disease, C. albicans traffics to and infects the brain by binding to gp96, a unique receptor that is expressed specifically on the surface of brain endothelial cells.
Vyšlo v časopise:
Mechanisms of Trafficking to the Brain. PLoS Pathog 7(10): e32767. doi:10.1371/journal.ppat.1002305
Kategorie:
Research Article
prolekare.web.journal.doi_sk:
https://doi.org/10.1371/journal.ppat.1002305
Souhrn
During hematogenously disseminated disease, Candida albicans infects most organs, including the brain. We discovered that a C. albicans vps51Δ/Δ mutant had significantly increased tropism for the brain in the mouse model of disseminated disease. To investigate the mechanisms of this enhanced trafficking to the brain, we studied the interactions of wild-type C. albicans and the vps51Δ/Δ mutant with brain microvascular endothelial cells in vitro. These studies revealed that C. albicans invasion of brain endothelial cells is mediated by the fungal invasins, Als3 and Ssa1. Als3 binds to the gp96 heat shock protein, which is expressed on the surface of brain endothelial cells, but not human umbilical vein endothelial cells, whereas Ssa1 binds to a brain endothelial cell receptor other than gp96. The vps51Δ/Δ mutant has increased surface expression of Als3, which is a major cause of the increased capacity of this mutant to both invade brain endothelial cells in vitro and traffic to the brain in mice. Therefore, during disseminated disease, C. albicans traffics to and infects the brain by binding to gp96, a unique receptor that is expressed specifically on the surface of brain endothelial cells.
Zdroje
1. WisplinghoffHBischoffTTallentSMSeifertHWenzelRP 2004 Nosocomial bloodstream infections in US hospitals: analysis of 24,179 cases from a prospective nationwide surveillance study. Clin Infect Dis 39 309 317
2. HornDLNeofytosDAnaissieEJFishmanJASteinbachWJ 2009 Epidemiology and outcomes of candidemia in 2019 patients: data from the prospective antifungal therapy alliance registry. Clin Infect Dis 48 1695 1703
3. ParkerJCJrMcCloskeyJJLeeRS 1981 Human cerebral candidosis--a postmortem evaluation of 19 patients. Hum Pathol 12 23 28
4. BenjaminDKJrStollBJGantzMGWalshMCSanchezPJ 2010 Neonatal candidiasis: epidemiology, risk factors, and clinical judgment. Pediatrics 126 e865 873
5. FaixRGChapmanRL 2003 Central nervous system candidiasis in the high-risk neonate. Semin Perinatol 27 384 392
6. BroadwellRDBaker-CairnsBJFridenPMOliverCVillegasJC 1996 Transcytosis of protein through the mammalian cerebral epithelium and endothelium. III. Receptor-mediated transcytosis through the blood-brain barrier of blood-borne transferrin and antibody against the transferrin receptor. Exp Neurol 142 47 65
7. CoureuilMLecuyerHScottMGBoularanCEnslenH 2010 Meningococcus Hijacks a beta2-adrenoceptor/beta-Arrestin pathway to cross brain microvasculature endothelium. Cell 143 1149 1160
8. HuangSHWassCFuQPrasadaraoNVStinsM 1995 Escherichia coli invasion of brain microvascular endothelial cells in vitro and in vivo: molecular cloning and characterization of invasion gene ibe10. Infect Immun 63 4470 4475
9. PrasadaraoNVSrivastavaPKRudrabhatlaRSKimKSHuangSH 2003 Cloning and expression of the Escherichia coli K1 outer membrane protein A receptor, a gp96 homologue. Infect Immun 71 1680 1688
10. ChangYCStinsMFMcCafferyMJMillerGFPareDR 2004 Cryptococcal yeast cells invade the central nervous system via transcellular penetration of the blood-brain barrier. Infect Immun 72 4985 4995
11. OrihuelaCJMahdaviJThorntonJMannBWooldridgeKG 2009 Laminin receptor initiates bacterial contact with the blood brain barrier in experimental meningitis models. J Clin Invest 119 1638 1646
12. RotrosenDEdwardsJEJrGibsonTRMooreJCCohenAH 1985 Adherence of Candida to cultured vascular endothelial cells: mechanisms of attachment and endothelial cell penetration. J Infect Dis 152 1264 1274
13. FillerSGSwerdloffJNHobbsCLuckettPM 1995 Penetration and damage of endothelial cells by Candida albicans. Infect Immun 63 976 983
14. SunJNSolisNVPhanQTBajwaJSKashlevaH 2010 Host cell invasion and virulence mediated by Candida albicans Ssa1. PLoS Pathog 6 e1001181
15. PhanQTMyersCLFuYSheppardDCYeamanMR 2007 Als3 is a Candida albicans invasin that binds to cadherins and induces endocytosis by host cells. PLoS Biol 5 e64
16. PhanQTFrattiRAPrasadaraoNVEdwardsJEJrFillerSG 2005 N-cadherin mediates endocytosis of Candida albicans by endothelial cells. J Biol Chem 280 10455 10461
17. ZhuWBoontheungPLooJAFillerSG 2010 Roles of HER2 and EGFR signaling in host cell invasion by Candida albicans, [Abstract 180B]. p. 127. Abstr 10th ASM Conf Candida Candidiasis Miami, Florida, United States 22–26 March 2010
18. LossinskyASJongAFialaMMukhtarMButtleKF 2006 The histopathology of Candida albicans invasion in neonatal rat tissues and in the human blood-brain barrier in culture revealed by light, scanning, transmission and immunoelectron microscopy. Histol Histopathol 21 1029 1041
19. JongAYStinsMFHuangSHChenSHKimKS 2001 Traversal of Candida albicans across human blood-brain barrier in vitro. Infect Immun 69 4536 4544
20. ParkHLiuYSolisNSpotkovJHamakerJ 2009 Transcriptional responses of Candida albicans to epithelial and endothelial cells. Eukaryot Cell 8 1498 1510
21. ConibearECleckJNStevensTH 2003 Vps51p mediates the association of the GARP (Vps52/53/54) complex with the late Golgi t-SNARE Tlg1p. Mol Biol Cell 14 1610 1623
22. ReggioriFWangCWStromhaugPEShintaniTKlionskyDJ 2003 Vps51 is part of the yeast Vps fifty-three tethering complex essential for retrograde traffic from the early endosome and Cvt vesicle completion. J Biol Chem 278 5009 5020
23. MacCallumDMOddsFC 2005 Temporal events in the intravenous challenge model for experimental Candida albicans infections in female mice. Mycoses 48 151 161
24. CannomRRMFrenchSWJohnstonDEdwardsJEJrFillerSG 2002 Candida albicans stimulates local expression of leukocyte adhesion molecules and cytokines in vivo. J Infect Dis 186 389 396
25. SheppardDCYeamanMRWelchWHPhanQTFuY 2004 Functional and structural diversity in the Als protein family of Candida albicans. J Biol Chem 279 30840 30849
26. SpellbergBIbrahimASEdwardsJEJrFillerSG 2005 Mice with disseminated candidiasis die of progressive sepsis. J Infect Dis 192 336 343
27. LaFayetteSLCollinsCZaasAKSchellWABetancourt-QuirozM 2010 PKC signaling regulates drug resistance of the fungal pathogen Candida albicans via circuitry comprised of Mkc1, calcineurin, and Hsp90. PLoS Pathog 6 e1001069
28. NichollsSMacCallumDMKaffarnikFASelwayLPeckSC 2011 Activation of the heat shock transcription factor Hsf1 is essential for the full virulence of the fungal pathogen Candida albicans. Fungal Genet Biol 48 297 305
29. CorreiaALermannUTeixeiraLCercaFBotelhoS 2010 Limited role of secreted aspartyl proteinases Sap1 to Sap6 in Candida albicans virulence and host immune response in murine hematogenously disseminated candidiasis. Infect Immun 78 4839 4849
30. NeteaMGVan Der GraafCAVonkAGVerschuerenIVan Der MeerJW 2002 The role of toll-like receptor (TLR) 2 and TLR4 in the host defense against disseminated candidiasis. J Infect Dis 185 1483 1489
31. van SprielABSofiMGartlanKHvan der SchaafAVerschuerenI 2009 The tetraspanin protein CD37 regulates IgA responses and anti-fungal immunity. PLoS Pathog 5 e1000338
32. RochaSFAdamsRH 2009 Molecular differentiation and specialization of vascular beds. Angiogenesis 12 139 147
33. LionakisMSLimJKLeeCCMurphyPM 2011 Organ-specific innate immune responses in a mouse model of invasive candidiasis. J Innate Immun 3 180 199
34. Martinez-LopezRMonteolivaLDiez-OrejasRNombelaCGilC 2004 The GPI-anchored protein CaEcm33p is required for cell wall integrity, morphogenesis and virulence in Candida albicans. Microbiology 150 3341 3354
35. Alonso-MongeRNavarro-GarciaFMoleroGDiez-OrejasRGustinM 1999 Role of the mitogen-activated protein kinase Hog1p in morphogenesis and virulence of Candida albicans. J Bacteriol 181 3058 3068
36. DalleFWachtlerBCoralieLHollandGBannertN 2010 Cellular interactions of Candida albicans with human oral epithelial cells and enterocytes. Cell Microbiol 12 248 271
37. LiuBYangYQiuZStaronMHongF 2010 Folding of Toll-like receptors by the HSP90 paralogue gp96 requires a substrate-specific cochaperone. Nat Commun 1 79
38. CabanesDSousaSCebriaALecuitMGarcia-del PortilloF 2005 Gp96 is a receptor for a novel Listeria monocytogenes virulence factor, Vip, a surface protein. Embo J 24 2827 2838
39. RechnerCKuhleweinCMullerASchildHRudelT 2007 Host glycoprotein Gp96 and scavenger receptor SREC interact with PorB of disseminating Neisseria gonorrhoeae in an epithelial invasion pathway. Cell Host Microbe 2 393 403
40. Di PasqualeGKaludovNAgbandje-McKennaMChioriniJA 2010 BAAV transcytosis requires an interaction with beta-1-4 linked- glucosamine and gp96. PLoS One 5 e9336
41. MaruvadaRArgonYPrasadaraoNV 2008 Escherichia coli interaction with human brain microvascular endothelial cells induces signal transducer and activator of transcription 3 association with the C-terminal domain of Ec-gp96, the outer membrane protein A receptor for invasion. Cell Microbiol 10 2326 2338
42. SukumaranSKMcNamaraGPrasadaraoNV 2003 Escherichia coli K-1 interaction with human brain micro-vascular endothelial cells triggers phospholipase C-gamma1 activation downstream of phosphatidylinositol 3-kinase. J Biol Chem 278 45753 45762
43. SukumaranSKPrasadaraoNV 2002 Regulation of protein kinase C in Escherichia coli K1 invasion of human brain microvascular endothelial cells. J Biol Chem 277 12253 12262
44. ClearyIAReinhardSMMillerCLMurdochCThornhillMH 2011 The Candida albicans adhesin Als3p is dispensable for virulence in the mouse model of disseminated candidiasis. Microbiology 157 Pt 6 1806 15
45. ColemanDAOhSHZhaoXZhaoHHutchinsJT 2009 Monoclonal antibodies specific for Candida albicans Als3 that immunolabel fungal cells in vitro and in vivo and block adhesion to host surfaces. J Microbiol Methods 78 71 78
46. GreenCBZhaoXHoyerLL 2005 Use of green fluorescent protein and reverse transcription-PCR to monitor Candida albicans agglutinin-like sequence gene expression in a murine model of disseminated candidiasis. Infect Immun 73 1852 1855
47. WilsonRBDavisDMitchellAP 1999 Rapid hypothesis testing with Candida albicans through gene disruption with short homology regions. J Bacteriol 181 1868 1874
48. ShenJGuoWKohlerJR 2005 CaNAT1, a heterologous dominant selectable marker for transformation of Candida albicans and other pathogenic Candida species. Infect Immun 73 1239 1242
49. LiXSSunJNOkamoto-ShibayamaKEdgertonM 2006 Candida albicans cell wall Ssa proteins bind and facilitate import of salivary histatin 5 required for toxicity. J Biol Chem 281 22453 22463
50. SanchezAAJohnstonDAMyersCEdwardsJEJrMitchellAP 2004 Relationship between Candida albicans virulence during experimental hematogenously disseminated Infection and endothelial cell damage In vitro. Infect Immun 72 598 601
51. PhanQTBelangerPHFillerSG 2000 Role of hyphal formation in interactions of Candida albicans with endothelial cells. Infect Immun 68 3485 3490
52. StinsMFNemaniPVWassCKimKS 1999 Escherichia coli binding to and invasion of brain microvascular endothelial cells derived from humans and rats of different ages. Infect Immun 67 5522 5525
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Hygiena a epidemiológia Infekčné lekárstvo LaboratóriumČlánok vyšiel v časopise
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