OALib Journal期刊
ISSN: 2333-9721
费用：99美元

投递稿件

查看量	下载量

相关文章
更多...

PLOS ONE 2009

A Novel Immune Evasion Strategy of Candida albicans: Proteolytic Cleavage of a Salivary Antimicrobial Peptide

DOI: 10.1371/journal.pone.0005039

Timothy F. Meiller, Bernhard Hube, Lydia Schild, Mark E. Shirtliff, Mark A. Scheper, Robert Winkler, Amy Ton, Mary Ann Jabra-Rizk

Full-Text Cite this paper Add to My Lib

Abstract:

Oropharyngeal candidiasis is an opportunistic infection considered to be a harbinger of AIDS. The etiologic agent Candida albicans is a fungal species commonly colonizing human mucosal surfaces. However, under conditions of immune dysfunction, colonizing C. albicans can become an opportunistic pathogen causing superficial or even life-threatening infections. The reasons behind this transition, however, are not clear. In the oral cavity, salivary antimicrobial peptides are considered to be an important part of the host innate defense system in the prevention of microbial colonization. Histatin-5 specifically has exhibited potent activity against C. albicans. Our previous studies have shown histatin-5 levels to be significantly reduced in the saliva of HIV+ individuals, indicating an important role for histatin-5 in keeping C. albicans in its commensal stage. The versatility in the pathogenic potential of C. albicans is the result of its ability to adapt through the regulation of virulence determinants, most notably of which are proteolytic enzymes (Saps), involved in tissue degradation. In this study, we show that C. albicans cells efficiently and rapidly degrade histatin-5, resulting in loss of its anti-candidal potency. In addition, we demonstrate that this cellular activity is due to proteolysis by a member of the secreted aspartic proteases (Sap) family involved in C. albicans pathogenesis. Specifically, the proteolysis was attributed to Sap9, in turn identifying histatin-5 as the first host-specific substrate for that isoenzyme. These findings demonstrate for the first time the ability of a specific C. albicans enzyme to degrade and deactivate a host antimicrobial peptide involved in the protection of the oral mucosa against C. albicans, thereby providing new insights into the factors directing the transition of C. albicans from commensal to pathogen, with important clinical implications for alternative therapy. This report characterizes the first defined mechanism behind the enhanced susceptibility of HIV+ individuals to oral candidiasis since the emergence of HIV.

References

[1]	Calderone RA, editor. (2002) Candida and Candidiasis. Washington: ASM Press.
[2]	Fidel PL Jr (2006) Candida-host interactions in HIV disease: relationships in oropharyngeal candidiasis. Adv Dent Res 19: 80–84.
[3]	Pfaller MA, Diekema DJ (2007) Epidemiology of invasive candidiasis: a persistent public health problem. Clin Microbiol Rev 20(1): 133–163.
[4]	Klein RS, et al. (1984) Oral candidiasis in high-risk patients as the initial manifestation of the acquired immunodeficiency syndrome. New Eng J Med 311: 354–358.
[5]	Lal K, et al. (1992) Pilot study comparing the salivary cationic protein concentrations in healthy adults and AIDS patients: correlation with antifungal activity. J AIDS Hum Retrovirol 5: 904–914.
[6]	de Repentigny L, Lewandowski D, Jolicoeur P (2004) Immunopathogenesis of oropharyngeal candidiasis in human immunodeficiency virus infection. Clin Microbiol Rev 17(4): 729–759.
[7]	Edgar WM (1992) Saliva: its secretion, composition and functions. Brit Dent J 172(8): 305–312.
[8]	Humphrey SP, Williamson RT (2001) A review of saliva: normal composition, flow, and function. J Prosthetic Dent 85(2): 162–169.
[9]	Helmerhorst EJ, Alagi AS, Siqueira WL, Oppenheim FG (2006) Oral fluid proteolytic effects on histatin 5 structure and function. Arch Oral Biol 51: 1061–1070.
[10]	Gyurko C, Lendenmann U, Helmerhorst EJ, Troxler RF, Oppenheim FG (2001) Killing of Candida albicans by histatin 5: cellular uptake and energy requirement. Antonie van Leeuwenhoek 79: 297–309.
[11]	Helmerhorst EJ, Troxler RF, Oppenheim FG (2001) The human salivary peptide histatin 5 exerts its antifungal activity through the formation of reactive oxygen species. Proc Natl Acad Sci USA 98(25): 14637–14642.
[12]	Edgerton M, et al. (1998) Candidacidal activity of salivary histatins. J Biol Chem 272(32): 20438–20447.
[13]	Oppenheim FG, et al. (1988) Histatins, a novel family of histidine-rich proteins in human parotid secretion. J Biol Chem 263(16): 7472–7477.
[14]	Jainkittivong A, Johnson DA, Yeh C-K (1998) The relationship between salivary histatin levels and oral yeast carriage. Oral Microbiol Immun 13: 181–187.
[15]	Helmerhorst EJ, et al. (1999) The cellular target of histatin 5 on Candida albicans is the energized mitochondrion. J Biol Chem 274(11): 7286–7291.
[16]	Jang WS, Li XS, Sun JN, Edgerton M (2008) The P-113 fragment of Histatin 5 requires a specific peptide sequence for intracellular translocation in Candida albicans which is independent of cell wall binding. Antimicrob Agents Chemother 52(2): 497–504.
[17]	Koshlukova SE, Araujo MWB, Baev D, Edgerton M (2000) Released ATP is an extracellular cytotoxic mediator in salivary histatin 5-induced killing of Candida albicans. Infect Immun 68(12): 6848–6856.
[18]	Li XS, Reddy MS, Baev D, Edgerton M (2003) Candida albicans Ssa1/2p is the cell envelope binding protein for human salivary histatin 5. J Biol Chem 278(31): 28553–28561.
[19]	Koshlukova SE, Lloyd TL, Araujo MWB, Edgerton M (1999) Salivary histatin 5 induces non-lytic release of ATP from Candida albicans leading to cell death. J Biol Chem 274(27): 18872–18879.
[20]	Mochon AB, Liu H (2008) The antimicrobial peptide histatin-5 causes a spatially restricted disruption on the Candida albicans surface allowing rapid entry of the peptide into the cytoplasm. PLoS Path 4(10): e1000190. doi:10.1371/journal.ppat.1000190.
[21]	Mandel ID, Barr CE, Turgeon L (1992) Longitudinal study of parotid saliva in HIV-1 infection. J Oral Path Med 21: 209–213.
[22]	Torres SR, Garzino-Demo A, Meeks V, Meiller TF, Jabra-Rizk MA (2008) Salivary Histatin-5 and oral fungal colonization in HIV+ individuals. Mycoses 52: 11–15.
[23]	Perlroth J, Choi B, Spellberg B (2007) Nosocomial fungal infections: epidemiology, diagnosis, and treatment. Med Mycol 45(4): 321–346.
[24]	Naglik JR, Albrecht A, Bader O, Hube B (2004) Candida albicans proteinases and host/pathogen interactions. Cell Microbiol 6(10): 915–926.
[25]	Naglik JR, Challacombe SJ, Hube B (2003) Candida albicans secreted aspartyl proteinases in virulence and pathogenesis. Microbiol Mol Biol Rev 67(3): 400–428.
[26]	de Bernardis F, et al. (1990) Evidence that members of the secretory aspartyl proteinases gene family (SAP), in particular SAP2, are virulence factors for Candida vaginitis. J Infect Dis 179: 201–208.
[27]	de Bernardis F, et al. (1996) Elevated aspartic proteinase secretion and experimental pathogenicity of Candida albicans isolates from oral cavities of subjects infected with human immunodeficiency virus. Infect Immun 64: 466–471.
[28]	Naglik JR, et al. (2008) Quantitative expression of the Candida albicans secreted aspartyl proteinase gene family in human oral and vaginal candidiasis. Microbiol 154(Pt. 11): 3266–3280.
[29]	Staib P, Kretschmar M, Nichteriein T, Hof H, Morschhauser J (2000) Differential activation of a Candida albicans virulence gene family during infection. Proc Natl Acad Sci USA 97: 6102–6107.
[30]	Hube B (1996) Candida albicans secreted aspartyl proteinases. Curr Top Med Mycol 7(1): 55–69.
[31]	Villar CC, Kashleva H, Nobile CJ, Mitchell AP, Dongari-Bagtzoglou A (2007) Mucosal tissue invasion by Candida albicans is associated with E-cadherin degradation, mediated by transcription factor rim 101p and protease Sap5p. Infect Immun 75(5): 2126–2135.
[32]	Albrecht A, et al. (2006) Glycosylphosphatidylinositol-anchored proteases of Candida albicans target proteins necessary for both cellular processes and host-pathogen interactions. J Biol Chem 281(2): 688–694.
[33]	Gagnon-Arsenault I, Pairise L, Tremblay J, Bourbonnais Y (2008) Activation mechanism, functional role and shedding of glycosylphosphatidylinositol-anchored Y ps 1 p at the Saccharomyces cerevisiae cell surface. Molec Microbiol 69(4): 982–993.
[34]	Ruissen ALA, et al. (2003) Internalisation and degradation of histatin 5 by Candida albicans. J Biol Chem 384(1): 183–190.
[35]	Kumamoto CA (2008) Niche-specific gene expression during C. albicans infection. Curr Opin Microbiol 11(4): 325–330.
[36]	Brown AJ, Odds FC, Gow NA (2007) Infection-related gene expression in Candida albicans. Curr Opin Microbiology 10(4): 307–313.
[37]	Hube B (2006) Infection-associated gene of Candida albicans. Future Microbiology 1: 209–218.
[38]	Xu L, Lal K, Santarpia RP III, Pollock JJ (1993) Salivary proteolysis of histidine-rich polypeptides and the antifungal activity of peptide degradation products. Arcf Oral Biol 38(4): 277–283.
[39]	Cannon RD, Chaffin WL (1999) Oral colonization by Candida albicans. Crit Rev Oral Biol Med 10(3): 359–383.
[40]	Chandra J, et al. (2001) Biofilm formation by the fungal pathogen Candida albicans: development, architecture, and drug resistance. J Bacteriol 183(18): 5385–5394.
[41]	Munro CA, Hube B (2002) Anti-fungal therapy at the HAART of viral therapy. Trends Microbiol 10(4): 177–178.
[42]	Hube B, et al. (1997) Disruption of each of the secreted aspartyl proteinase genes SAP1, SAP2, and SAP3 of Candida albicans attenuates virulence. Infect Immun 65(9): 3529–3538.
[43]	Kretschmar M, Felk A, Staib P, Schaller M, He？ D, et al. (2002) Individual acidic aspartic proteinases (Saps)1-6 of Candida albicans are not indispensable for invasion and colonisation of the gastrointestinal tract in mice. Microb Path 32: 61–70.
[44]	Sanglard D, Hube B, Monod M, Odds FC, Gow NAR (1997) A triple deletion of the secreted aspartyl proteinase genes SAP4, SAP5, and SAP6 of Candida albicans causes attenuated virulence. Infect Immun 65(9): 3539–3546.
[45]	Borg-von Zepelin M, et al. (1998) The expression of the secreted aspartyl proteinases Sap4 to Sap6 from Candida albicans in murine macrophages. Mol Microbiol 28(3): 543–54.

Full-Text

Contact Us

service@oalib.com

QQ:3279437679

WhatsApp +8615387084133