Secreted Aspartyl Proteases Family: A Perspective Review on the Regulation Of Fungal Pathogenesis

Kulshrestha, Anmol; Gupta, Pratima

doi:10.2217/fmb-2022-0143

Cited by 13 publications

(4 citation statements)

References 66 publications

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“…Our findings are aligned with the existing literature, as it is known that when C. albicans cells invade host tissues, they must surpass surface barriers like skin and mucosa [ 45 ]. In this context, Saps aid in penetration by cleaving extracellular matrix proteins such as laminin, fibronectin, collagen, and mucin [ 46 , 47 ]. Studies have also shown that C. albicans strains can both adhere to and enzymatically degrade mucins in oral cavities and the gastrointestinal tract, thereby modulating Candida populations [ 48 , 49 ].…”

Section: Resultsmentioning

confidence: 99%

Saps1–3 Antigens in Candida albicans: Differential Modulation Following Exposure to Soluble Proteins, Mammalian Cells, and Infection in Mice

Barbosa,

Gonçalves,

Ramos

et al. 2024

Infectious Disease Reports

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The secreted aspartic peptidases (Saps) of Candida albicans play crucial roles in various steps of fungal–host interactions. Using a flow cytometry approach, this study investigated the expression of Saps1–3 antigens after (i) incubation with soluble proteins, (ii) interaction with mammalian cells, and (iii) infection in immunosuppressed BALB/c mice. Supplementation strategies involving increasing concentrations of bovine serum albumin (BSA) added to yeast carbon base (YCB) medium as the sole nitrogenous source revealed a positive and significant correlation between BSA concentration and both the growth rate and the percentage of fluorescent cells (%FC) labeled with anti-Saps1–3 antibodies. Supplementing the YCB medium with various soluble proteins significantly modulated the expression of Saps1–3 antigens in C. albicans. Specifically, immunoglobulin G, gelatin, and total bovine/human sera significantly reduced the %FC, while laminin, human serum albumin, fibrinogen, hemoglobin, and mucin considerably increased the %FC compared to BSA. Furthermore, co-cultivating C. albicans yeasts with either live epithelial or macrophage cells induced the expression of Saps1–3 antigens in 78% (mean fluorescence intensity [MFI] = 152.1) and 82.7% (MFI = 178.2) of the yeast cells, respectively, compared to BSA, which resulted in 29.3% fluorescent cells (MFI = 50.9). Lastly, the yeasts recovered from the kidneys of infected immunosuppressed mice demonstrated a 4.8-fold increase in the production of Saps1–3 antigens (MFI = 246.6) compared to BSA, with 95.5% of yeasts labeled with anti-Saps1–3 antibodies. Altogether, these results demonstrated the positive modulation of Saps’ expression in C. albicans by various key host proteinaceous components, as well as by in vitro and in vivo host challenges.

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Section: Resultsmentioning

confidence: 99%

Saps1–3 Antigens in Candida albicans: Differential Modulation Following Exposure to Soluble Proteins, Mammalian Cells, and Infection in Mice

Barbosa,

Gonçalves,

Ramos

et al. 2024

Infectious Disease Reports

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“…Additionally, geraniol treatment was able to downregulate the PLB-1 and SAP-1 gene expression. Those enzymes have a critical role in fungal pathogeneses, such as yeast-hyphal transformation, adhesion, and tissue invasion ( Kumar et al, 2017 ; D’Enfert et al, 2021 ; Kulshrestha and Gupta, 2023 ).…”

Section: Discussionmentioning

confidence: 99%

Monoterpene antifungal activities: evaluating geraniol, citronellal, and linalool on Candida biofilm, host inflammatory responses, and structure–activity relationships

Vasconcelos,

Lee,

Abuna

et al. 2024

Front. Pharmacol.

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Introduction: Despite the rising concern with fungal resistance, a myriad of molecules has yet to be explored. Geraniol, linalool, and citronellal are monoterpenes with the same molecular formula (C10H18O), however, neither the effect of these compounds on inflammatory axis induced by Candida spp. nor the antibiofilm Structure-Activity Relationship (SAR) have been well-investigated. Herein we analyzed geraniol, linalool and citronellal antifungal activity, cytotoxicity, and distinctive antibiofilm SAR, also the influence of geraniol on Candida spp induced dysregulated inflammatory axis, and in vivo toxicity.Methods: Minimal inhibitory (MIC) and fungicidal (MFC) concentrations against Candida spp were defined, followed by antibiofilm activity (CFU–colony forming unit/mL/g of dry weight). Cytotoxic activity was assessed using human monocytes (THP-1) and oral squamous cell (TR146). Geraniol was selected for further analysis based on antifungal, antibiofilm and cytotoxic results. Geraniol was tested using a dual-chamber co-culture model with TR146 cells infected with C. albicans, and THP-1 cells, used to mimic oral epithelium upon fungal infection. Expression of Candida enzymes (phospholipase–PLB and aspartyl proteases–SAP) and host inflammatory cytokines (interleukins: IL-1β, IL-6, IL-17, IL-18, IL-10, and Tumor necrosis factor–TNF) were analyzed. Lastly, geraniol in vivo toxicity was assessed using Galleria mellonella.Results: MIC values obtained were 1.25–5 mM/mL for geraniol, 25-100 mM/mL for linalool, and 100–200 mM/mL for citronellal. Geraniol 5 and 50 mM/mL reduced yeast viability during biofilm analysis, only 500 mM/mL of linalool was effective against a 72 h biofilm and no biofilm activity was seen for citronellal. LD50 for TR146 and THP-1 were, respectively: geraniol 5.883 and 8.027 mM/mL; linalool 1.432 and 1.709 mM/mL; and citronellal 0.3006 and 0.1825 mM/mL. Geraniol was able to downregulate expression of fungal enzymes and host pro-inflammatory cytokines IL-1β, IL-6, and IL-18. Finally, safety in vivo parameters were observed up to 20 mM/Kg.Discussion: Despite chemical similarities, geraniol presented better antifungal, antibiofilm activity, and lower cytotoxicity when compared to the other monoterpenes. It also showed low in vivo toxicity and capacity to downregulate the expression of fungal enzymes and host pro-inflammatory cytokines. Thus, it can be highlighted as a viable option for oral candidiasis treatment.

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“…Furthermore, they could be engaged in immune evasion, adhesion, hyphal development, and biofilm formation. 20 They include 10 members that are sequentially expressed at different stages of infection and are encoded by the aspartyl proteinases (SAP) gene family. 21 The SAP2 protein has been widely studied and has been shown to play a crucial role in vaginal infection.…”

Section: Introductionmentioning

confidence: 99%

Biofilm Formation and Aspartyl Proteinase Activity and Their Association with Azole Resistance Among Candida albicans Causing Vulvovaginal Candidiasis, Egypt

Gerges,

Fahmy,

Hosny

et al. 2023

IDR

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Background Candida albicans ( C. albicans ) is a major cause of vulvovaginal candidiasis (VVC), a condition that is commonly treated with azole agents. Biofilm formation and aspartyl proteinase production are important virulence factors that could be linked to azole resistance in C. albicans impeding therapy. Aim To find out the association of both factors with azole resistance among C. albicans isolated from VVC cases in Egyptian nonpregnant women of childbearing age. Patients and Methods In a cross-sectional study, C. albicans was isolated from nonpregnant females diagnosed clinically as having VVC during a 1-year study period. Susceptibility to azole agents was tested using the disc diffusion method. Biofilm formation and aspartyl proteinase production were assessed phenotypically. Additionally, two biofilm-related genes ( ALS1 and HWP1 ) and three proteinase genes ( SAP2, SAP4 , and SAP6 ) were screened for using polymerase chain reaction (PCR). Results Among 204 C. albicans isolates, azole resistance ratios were as follows: voriconazole (30.4%), itraconazole (17.6%), fluconazole (11.3%) and econazole (6.4%). Biofilm-producing capacity was detected in 63.2% of isolates, and 63.2% were proteinase producers. The frequencies of ALS1 and HWP1 were 69.6% and 74.5%, respectively, while SAP2, SAP4 , and SAP6 were 69.2%, 88.7%, and 64.7%, respectively. Biofilm formation was significantly associated with azole resistance (P < 0.001 for each tested azole agent) as was proteinase production (P < 0.001 for fluconazole, voriconazole, and econazole resistance and P = 0.047 for itraconazole). Conclusion Among nonpregnant Egyptian women of childbearing age, azole resistance in C. albicans causing VVC is significantly associated with biofilm formation and proteinase production. The development of new therapeutic agents that can target these factors is warranted.

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Secreted Aspartyl Proteases Family: A Perspective Review on the Regulation Of Fungal Pathogenesis

Cited by 13 publications

References 66 publications

Saps1–3 Antigens in Candida albicans: Differential Modulation Following Exposure to Soluble Proteins, Mammalian Cells, and Infection in Mice

Saps1–3 Antigens in Candida albicans: Differential Modulation Following Exposure to Soluble Proteins, Mammalian Cells, and Infection in Mice

Monoterpene antifungal activities: evaluating geraniol, citronellal, and linalool on Candida biofilm, host inflammatory responses, and structure–activity relationships

Biofilm Formation and Aspartyl Proteinase Activity and Their Association with Azole Resistance Among Candida albicans Causing Vulvovaginal Candidiasis, Egypt

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