The role ofCandida albicans secreted aspartic proteinase in the development of candidoses

Hoegl, L.; Ollert, Markus; Körting, Hans Christian

doi:10.1007/bf01575445

Cited by 57 publications

(47 citation statements)

References 68 publications

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“…For more details, the reader is guided to review articles on discovery and characterization of the SAP gene family; structure, processing, activation and regulation; purification, activity and enzymatic properties; and in vitro SAP gene expression in culture medium (50,88,94,95,97,98,145,163,185,227). The present review is restricted to studies addressing the relationship between proteinase production and C. albicans pathogenesis.…”

Section: Candida Sap Familymentioning

confidence: 99%

Candida albicansSecreted Aspartyl Proteinases in Virulence and Pathogenesis

Naglik

Challacombe

Hube

2003

Microbiol Mol Biol Rev

1,027

970

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Candida albicans is the most common fungal pathogen of humans and has developed an extensive repertoire of putative virulence mechanisms that allows successful colonization and infection of the host under suitable predisposing conditions. Extracellular proteolytic activity plays a central role in Candida pathogenicity and is produced by a family of 10 secreted aspartyl proteinases (Sap proteins). Although the consequences of proteinase secretion during human infections is not precisely known, in vitro, animal, and human studies have implicated the proteinases in C. albicans virulence in one of the following seven ways: (i) correlation between Sap production in vitro and Candida virulence, (ii) degradation of human proteins and structural analysis in determining Sap substrate specificity, (iii) association of Sap production with other virulence processes of C. albicans, (iv) Sap protein production and Sap immune responses in animal and human infections, (v) SAP gene expression during Candida infections, (vi) modulation of C. albicans virulence by aspartyl proteinase inhibitors, and (vii) the use of SAP-disrupted mutants to analyze C. albicans virulence. Sap proteins fulfill a number of specialized functions during the infective process, which include the simple role of digesting molecules for nutrient acquisition, digesting or distorting host cell membranes to facilitate adhesion and tissue invasion, and digesting cells and molecules of the host immune system to avoid or resist antimicrobial attack by the host. We have critically discussed the data relevant to each of these seven criteria, with specific emphasis on how this proteinase family could contribute to Candida virulence and pathogenesis

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Section: Candida Sap Familymentioning

confidence: 99%

Candida albicansSecreted Aspartyl Proteinases in Virulence and Pathogenesis

Naglik

Challacombe

Hube

2003

Microbiol Mol Biol Rev

1,027

970

View full text Add to dashboard Cite

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“…For example, Candida is known to have at least seven genes that encode secreted aspartic proteinases (9,33). Aspergilli that cause invasive aspergillosis are known to express genes that encode serine proteinases (34)(35)(36)(37), metalloproteinases (38)(39)(40), and aspartic proteinases (41).…”

Section: Discussionmentioning

confidence: 99%

“…A variety of lines of evidence for their role in pathogenesis, including the correlation between the level of such enzymes and virulence, immunocytochemical evidence for the secretion of the enzyme during infection, protection of the host by inhibition of the enzymes with selective inhibitors or specific antibodies, and enhancement of virulence by gene transfer, have been challenged on the basis of the results of disruption experiments on genes that encode cutinase and cell wall-degrading enzymes (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14). In the case of animal pathogens, single and double proteinase gene disruption failed to show a clear decrease in virulence (15)(16)(17).…”

mentioning

confidence: 99%

Requirement for either a host- or pectin-induced pectate lyase for infection of Pisum sativum by Nectria hematococca

Rogers

Kim

Guo

et al. 2000

Proc. Natl. Acad. Sci. U.S.A.

128

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Fungal pathogens usually have multiple genes that encode extracellular hydrolytic enzymes that may degrade the physical barriers in their hosts during the invasion process. Nectria hematococca, a plant pathogen, has two inducible pectate lyase (PL) genes (pel) encoding PL that can help degrade the carbohydrate barrier in the host. pelA is induced by pectin, whereas pelD is induced only in planta. We show that the disruption of either the pelA or pelD genes alone causes no detectable decrease in virulence. Disruption of both pelA and pelD drastically reduces virulence. Complementation of the double disruptant with pelD gene, or supplementation of the infection droplets of the double disruptant with either purified enzyme, PLA, or PLD, caused a recovery in virulence. These results show that PL is a virulence factor. Thus, we demonstrate that disruption of all functionally redundant genes is required to demonstrate the role of host barrier-degrading enzymes in pathogenesis and that dismissal of the role of such enzymes based on the effects of single-gene disruption may be premature.

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“…virulence factors, such as the secreted aspartyl proteases (Sap) (Hoegl et al, 1996 ;Hube et al, 1997 ;, extracellular phospholipases (Ghannoum, 2000), Int1p (Gale et al, 1998) and the outer mannoprotein Hwp1 (Staab et al, 1999), have been identified, and many of these are found either on the cell surface or in the extracellular environment. However, little is known about the means by which these virulenceassociated proteins are processed and secreted.…”

Section: Introductionmentioning

confidence: 99%

Overexpression of a dominant-negative allele of YPT1 inhibits growth and aspartyl protease secretion in Candida albicans The GenBank accession number for the C. albicans YPT1 sequence reported in this paper is AF330211.

et al. 2001

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To investigate the pre-Golgi secretion pathway in the pathogenic yeast Candida albicans, we cloned the C. albicans homologue of the Saccharomyces cerevisiae protein secretion gene YPT1. The C. albicans YPT1 ORF contained a 624 bp intronless ORF encoding a deduced protein of 207 aa and 23 kDa. This deduced protein was 77 % identical to S. cerevisiae Ypt1 protein (Ypt1p) and it contained GTP-binding domains that are conserved among all known ras-like GTPases. Multicopy plasmids containing C. albicans YPT1 complemented the temperature-sensitive S. cerevisiae ypt1 (A136D) mutation. One chromosomal YPT1 allele in C. albicans CAI4 was readily disrupted by homologous gene targeting, but attempts to disrupt the second allele yielded no viable null mutants. Since this suggested that C. albicans YPT1 may be essential, a mutant ypt1 allele was constructed encoding the amino acid substitution analogous to the N121I substitution in a known trans-dominant inhibitor of S. cerevisiae Ypt1p. Next, a GAL1-regulated plasmid was used to express the mutant ypt1(N121I) allele in C. albicans CAI4. Ten of 11 transformants tested grew normally in glucose and poorly in galactose, and plasmid curing restored growth to wild-type levels. When these transformants were incubated in galactose, secretion of aspartyl proteinase (Sap) was inhibited and membranebound secretory vesicles accumulated intracellularly. These results imply that C. albicans YPT1 is required for growth and protein secretion, and they confirm the feasibility of using inducible dominant-negative alleles to define the functions of essential genes in C. albicans.

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The role ofCandida albicans secreted aspartic proteinase in the development of candidoses

Cited by 57 publications

References 68 publications

Candida albicansSecreted Aspartyl Proteinases in Virulence and Pathogenesis

Candida albicansSecreted Aspartyl Proteinases in Virulence and Pathogenesis

Requirement for either a host- or pectin-induced pectate lyase for infection of Pisum sativum by Nectria hematococca

Overexpression of a dominant-negative allele of YPT1 inhibits growth and aspartyl protease secretion in Candida albicans The GenBank accession number for the C. albicans YPT1 sequence reported in this paper is AF330211.

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