title: Candida albicans yeast and hyphae are discriminated by MAPK signaling in vaginal epithelial cells.
abstract: We previously reported that a bi-phasic innate immune MAPK response, constituting activation of the mitogen-activated protein kinase (MAPK) phosphatase MKP1 and c-Fos transcription factor, discriminates between the yeast and hyphal forms of Candida albicans in oral epithelial cells (ECs). Since the vast majority of mucosal Candida infections are vaginal, we sought to determine whether a similar bi-phasic MAPK-based immune response was activated by C. albicans in vaginal ECs. Here, we demonstrate that vaginal ECs orchestrate an innate response to C. albicans via NF-κB and MAPK signaling pathways. However, unlike in oral ECs, the first MAPK response, defined by c-Jun transcription factor activation, is delayed until 2 h in vaginal ECs but is still independent of hypha formation. The 'second' or 'late' MAPK response, constituting MKP1 and c-Fos transcription factor activation, is identical to oral ECs and is dependent upon both hypha formation and fungal burdens. NF-κB activation is immediate but independent of morphology. Furthermore, the proinflammatory response in vaginal ECs is different to oral ECs, with an absence of G-CSF and CCL20 and low level IL-6 production. Therefore, differences exist in how C. albicans activates signaling mechanisms in oral and vaginal ECs; however, the activation of MAPK-based pathways that discriminate between yeast and hyphal forms is retained between these mucosal sites. We conclude that this MAPK-based signaling pathway is a common mechanism enabling different human epithelial tissues to orchestrate innate immune responses specifically against C. albicans hyphae.
authors.affiliation: Department of Oral Medicine, Pathology and Immunology, King's College London Dental Institute, King's College London, London, United Kingdom.
authors.forename: David L
authors.initials: DL
authors.lastname: Moyes
authors.forename: Celia
authors.initials: C
authors.lastname: Murciano
authors.forename: Manohursingh
authors.initials: M
authors.lastname: Runglall
authors.forename: Ayesha
authors.initials: A
authors.lastname: Islam
authors.forename: Selvam
authors.initials: S
authors.lastname: Thavaraj
authors.forename: Julian R
authors.initials: JR
authors.lastname: Naglik
mesh_terms: D002176:Candida albicans / Q000276:immunology*; D054418:Chemokine CCL20; D004847:Epithelial Cells / Q000378:metabolism / Q000382:microbiology; D005260:Female; D016179:Granulocyte Colony-Stimulating Factor; D006801:Humans; D025301:Hyphae / Q000276:immunology*; D007113:Immunity, Innate; D015850:Interleukin-6; D020935:MAP Kinase Signaling System / Q000276:immunology*; D009061:Mouth Mucosa / Q000276:immunology / Q000382:microbiology; D016328:NF-kappa B / Q000276:immunology; D014621:Vagina / Q000276:immunology / Q000382:microbiology* / Q000473:pathology
chemical_list: C108355:CCL20 protein, human; D054418:Chemokine CCL20; D015850:Interleukin-6; D016328:NF-kappa B; D016179:Granulocyte Colony-Stimulating Factor
references.citation: Infect Immun. 2010 Dec;78(12):5126-37
references.pmid: 20823201
references.citation: Infect Immun. 2006 Jun;74(6):3213-21
references.pmid: 16714548
references.citation: Microbiology (Reading). 2008 Nov;154(Pt 11):3266-3280
references.pmid: 18957581
references.citation: J Exp Med. 2011 Aug 29;208(9):1889-900
references.pmid: 21825016
references.citation: Mol Gen Genet. 1984;198(2):179-82
references.pmid: 6394964
references.citation: Nat Rev Immunol. 2004 Jan;4(1):1-23
references.pmid: 14661066
references.citation: Nat Rev Immunol. 2010 Feb;10(2):89-102
references.pmid: 20081871
references.citation: Am J Reprod Immunol. 2007 Jan;57(1):2-12
references.pmid: 17156186
references.citation: J Infect Dis. 1999 Sep;180(3):802-10
references.pmid: 10438369
references.citation: Ann N Y Acad Sci. 1988;544:547-57
references.pmid: 3063184
references.citation: Infect Immun. 1998 Mar;66(3):1273-5
references.pmid: 9488427
references.citation: Ann N Y Acad Sci. 2006 Aug;1072:52-61
references.pmid: 17057190
references.citation: Science. 1999 Dec 24;286(5449):2514-7
references.pmid: 10617468
references.citation: Infect Immun. 2004 May;72(5):2939-46
references.pmid: 15102806
references.citation: Int J Biochem Cell Biol. 1998 Oct;30(10):1075-9
references.pmid: 9785472
references.citation: Cell Host Microbe. 2010 Sep 16;8(3):225-35
references.pmid: 20833374
references.citation: J Clin Invest. 2007 Dec;117(12):3664-72
references.pmid: 17992260
references.citation: Infect Immun. 2002 Dec;70(12):7081-8
references.pmid: 12438389
references.citation: J Clin Invest. 2006 Jun;116(6):1642-50
references.pmid: 16710478
references.citation: Med Mycol. 1999 Aug;37(4):251-9
references.pmid: 10421860
references.citation: EMBO J. 2001 Sep 3;20(17):4742-52
references.pmid: 11532938
references.citation: Nat Protoc. 2006;1(6):2767-73
references.pmid: 17406503
references.citation: Cell. 1997 Sep 5;90(5):939-49
references.pmid: 9298905
references.citation: Trends Microbiol. 2004 May;12(5):220-7
references.pmid: 15120141
references.citation: Oral Microbiol Immunol. 2003 Jun;18(3):165-70
references.pmid: 12753468
references.citation: J Invest Dermatol. 2002 Apr;118(4):652-7
references.pmid: 11918712
references.citation: Eur Cytokine Netw. 2007 Mar;18(1):38-43
references.pmid: 17400537
references.citation: J Med Microbiol. 2003 Aug;52(Pt 8):623-632
references.pmid: 12867554
references.citation: J Infect Dis. 2001 Dec 1;184(11):1489-93
references.pmid: 11709796
references.citation: Med Mycol. 2004 Dec;42(6):531-41
references.pmid: 15682642
references.citation: Immunity. 2006 Feb;24(2):191-201
references.pmid: 16473831
references.citation: Microbiology (Reading). 2004 Sep;150(Pt 9):2807-2813
references.pmid: 15347740
references.citation: Infect Immun. 1999 Jun;67(6):3135-40
references.pmid: 10338532
references.citation: Annu Rev Biochem. 1999;68:821-61
references.pmid: 10872467
references.citation: Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 1997 Oct;84(4):372-80
references.pmid: 9347501
references.citation: Cell Microbiol. 2007 Dec;9(12):2938-54
references.pmid: 17645752
references.citation: Nat Rev Immunol. 2007 Mar;7(3):202-12
references.pmid: 17318231
references.citation: Yeast. 2000 Mar 15;16(4):325-7
references.pmid: 10669870
references.citation: Exp Cell Res. 1999 Nov 25;253(1):180-5
references.pmid: 10579922
references.citation: Curr Opin Infect Dis. 2005 Apr;18(2):107-11
references.pmid: 15735412