<i>Candida albicans</i>Secreted Aspartyl Proteinases in Virulence and Pathogenesis

Naglik, Julian R.; Challacombe, Stephen; Hube, Bernhard

doi:10.1128/mmbr.67.3.400-428.2003

Cited by 1,028 publications

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“…Indeed Sap2 and Sap6 provide the second signal causing direct NLRP3 activation, as demonstrated by their capacity of inducing caspase-1-dependent IL-1β production. These data suggest that Saps can genuinely activate the inflammasome, rather than spuriously affecting inflammasome auto-activation.There is overwhelming experimental, and a certain amount of clinical evidence that Saps are important factors of C. albicans virulence [5,15,[51][52][53][54]. The demonstration that proinflammatory cytokine production is induced by Saps through inflammasome activation implies a new role for these virulence factors related to their structural features.…”

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“…Spleen tyrosine kinase (Syk) coupled to fungal pattern recognition receptors, such as Dectin-1, controls both pro-IL-1β synthesis and the activation of the inflammasome after cell stimulation with C. albicans [13]. IL-1β and IL-18, which are both induced by activation of the inflammasome, are involved in the initiation of the adaptive Th1 and Th17 cellular responses to C. albicans [14].To investigate whether the inflammasome activation is triggered by Saps, we selected Sap2 and Sap6 as members of two Sap subfamilies, Sap1-3 and Sap4-6 respectively, which differ in their biological properties and potential roles in different types of C. albicans infections [5,15]. …”

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“…In selected experiments monocytes were stimulated with 12.5 μg/mL of diacylated lipoprotein FSL-1 (Pam2CGDPKHPKSF, InvivoGen) or with flagellin from Bacillus subtilis (100 ng/mL, InvivoGen). In selected experiments cells were pretreated with nystatin (5 μg/mL, Sigma), chlorpromazine (90,45,15 …”

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Secreted aspartic proteases of Candida albicans activate the NLRP3 inflammasome

et al. 2013

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In a recent report, we demonstrated that distinct members of the secreted aspartic protease (Sap) family of Candida albicans are able to induce secretion of proinflammatory cytokines by human monocytes, independently of their proteolytic activity and specific pH optima. In particular, C. albicans Sap2 and Sap6 potently induced IL-1β, TNF-α, and IL-6 production. Here, we demonstrate that Sap2 and Sap6 proteins trigger IL-1β and IL-18 production through inflammasome activation. This occurs via NLRP3 and caspase-1 activation, which cleaves pro-IL-1β into secreted bioactive IL-1β, a cytokine that was induced by Saps in monocytes, in monocyte-derived macrophages and in dendritic cells. Downregulation of NLRP3 by RNA interference strongly reduced the secretion of bioactive IL-1β. Inflammasome activation required Sap internalization via a clathrin-dependent mechanism, intracellular induction of K + efflux, and ROS production. Inflammasome activation of monocytes induced by Sap2 and Sap6 differed from that induced by LPS-ATP in several aspects. Our data reveal novel immunoregulatory mechanisms of C. albicans and suggest that Saps contribute to the pathogenesis of candidiasis by fostering rather than evading host immunity.Keywords: Aspartic proteases r C. albicans r IL-1β r Inflammasome r Virulence factor IntroductionCandida albicans is a commensal fungus that colonizes human mucosal surfaces such as the vaginal and gastrointestinal tracts without causing harm. However, under conditions of primary or secondary immunodeficiency, this yeast can cause opportunistic infections such as mucosal inflammation and systemic sepsis [1]. The mortality rate associated with invasive candidiasis Correspondence: Dr. Anna Vecchiarelli e-mail: vecchiar@unipg.it has been reported to be as high as 40-50% [2]. Candida species are the fourth most common pathogens isolated from nosocomial bloodstream infections in the USA and Europe [3]. Although the immune status of the host plays a key role in the prevention or pathogenesis of C. albicans infections, a number of virulence attributes of C. albicans, such as factors that mediate adhesion, enzyme secretion, or hyphal formation, contribute to the disease process [4]. Particularly, the secretion of aspartic proteases (Saps), * These authors contributed equally to this work.C 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.eji-journal.eu 680Donatella Pietrella et al. Eur. J. Immunol. 2013. 43: 679-692 which are encoded by a gene family with ten members, has long been recognized as a virulence-associated trait of this pathogenic yeast [5].We recently reported that various members of the Sap family, including Sap1, Sap2, Sap3, and Sap6, have different abilities to induce secretion of pro-inflammatory cytokines by human monocytes via Akt/NF-κB activation. Sap1, Sap2, and Sap6 potently induced IL-1β, TNF-α, and IL-6 production. Importantly, Sapinduced cytokine production was independent of the proteolytic activity and of the optimal pH for the individual Sap activities [6]. These data suggest ...

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Secreted aspartic proteases of Candida albicans activate the NLRP3 inflammasome

et al. 2013

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“…These enzymes may be required for nutrient acquisition, distortion of host cell membranes to assist adhesion and tissue damage, and digestion of components of the host immune system to divert antimicrobial attack. 11 All studies of putative virulence factors in C. albicans must be analyzed in the context of the immune status of the host, since in the absence of a compromised immune state, even the so-called virulent forms are not likely to cause infection. Interestingly, C. albicans has the ability to exploit a range of weakness in the host defense system, as illustrated by the spectrum of infections observed in humans.…”

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Genetic analysis of innate immunity in resistance to Candida albicans

2004

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Systemic candidiasis is a significant cause of nosocomial infections and the mechanisms of defense against Candida albicans in humans remain poorly understood. Studies in animal models have demonstrated the importance of innate immunity in controlling the response to infection. Although Th1 cytokines have been shown to direct the overall outcome of infection, the precise role of the Th1/Th2 response and, more generally, the adaptive immune response as a whole, in systemic candidiasis, appears to apply mainly to the development of resistance to reinfection. A genetic approach to the identification of host factors regulating pathogenesis and susceptibility to C. albicans infection has been used in humans and in mouse models of infection. Mouse mutants bearing experimentally induced mutations in specific genes have provided a systematic tool for directly assessing the role of individual proteins in C. albicans susceptibility. Inbred mouse strains have been valuable in showcasing the spectrum of naturally occurring variations in initial susceptibility to infection, and type of disease developed. Crosses between resistant and susceptible strains have led to the detection of additional gene effects affecting innate immunity. Of particular interest is the major effect of a naturally occurring loss-of-function mutation in the C5 complement component that has become fixed in many inbred strains. These and other studies have shown that both a functional complement pathway and robust inflammatory response are critical for resistance to C. albicans.

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“…Secreted aspartic proteinases, together with lipases and phospholipases, facilitate yeast adhesion in the initial stages of infection, enable penetration of the pathogens into host tissues, and provide a source of nutrients for the pathogen by breaking down host molecules. [6][7][8] Pathogenic Candida spp. usually possess a gene family encoding secreted aspartic proteinases (SAPs).…”

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Evidence for the presence of proteolytically active secreted aspartic proteinase 1 of Candida parapsilosis in the cell wall

et al. 2011

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Pathogenic yeasts of the genus Candida produce secreted aspartic proteinases, which are known to enhance virulence. We focused on Sapp1p proteinase secreted by Candida parapsilosis and studied the final stage of its passage through the cell wall and release into the extracellular environment. We found that Sapp1p displays enzyme activity prior to secretion, and therefore, it is probably fully folded within the upper layer of the cell wall. The positioning of cell surface-associated Sapp1p was detected by cell wall protein labeling using biotinylation agents, extraction of cell wall proteins by b-mercaptoethanol, immunochemical detection, and mass spectrometry analysis. All lysine residues present in the structure of soluble, purified Sapp1p were labeled with biotin. In contrast, the accessibility of individual lysines in cell wall-associated Sapp1p varied with the exception of four lysine residues that were biotinylated in all experiments performed, suggesting that Sapp1p has a preferred orientation in the cell wall. As the molecular weight of this partially labeled Sapp1p did not differ among the experiments, we can assume that the retaining of Sapp1p in the cell wall is not a totally random process and that pathogenic yeasts might use this cell-associated proteinase activity to enhance degradation of appropriate substrates.

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Candida albicansSecreted Aspartyl Proteinases in Virulence and Pathogenesis

Cited by 1,028 publications

References 253 publications

Secreted aspartic proteases of Candida albicans activate the NLRP3 inflammasome

Secreted aspartic proteases of Candida albicans activate the NLRP3 inflammasome

Genetic analysis of innate immunity in resistance to Candida albicans

Evidence for the presence of proteolytically active secreted aspartic proteinase 1 of Candida parapsilosis in the cell wall

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