Sequence Variation of Candida albicans Sap2 Enhances Fungal Pathogenicity via Complement Evasion and Macrophage M2‐Like Phenotype Induction

Abstract

Candida albicans (C. albicans) is an opportunistic pathogen increasingly causing candidiasis worldwide. This study aims to investigate the pattern of systemic immune responses triggered by C. albicans with disease associated variation of Sap2, identifying the novel evasion strategies utilized by clinical isolates. Specifically, a variation in clinical isolates is identified at nucleotide position 817 (G to T). This homozygous variation causes the 273rd amino acid exchange from valine to leucine, close to the proteolytic activation center of Sap2. The mutant (Sap2‐273L) generated from SC5314 (Sap2‐273V) background carrying the V273L variation within Sap2 displays higher pathogenicity. In comparison to mice infected with Sap2‐273V strain, mice infected with Sap2‐273L exhibit less complement activation indicated by less serum C3a generation and weaker C3b deposition in the kidney. This inhibitory effect is mainly achieved by Sap2273L‐mediated stronger degradation of C3 and C3b. Furthermore, mice infected with Sap2‐273L strain exhibit more macrophage phenotype switching from M0 to M2‐like and more TGF‐β release which further influences T cell responses, generating an immunosuppressed cellular microenvironment characterized by more Tregs and exhausted T cell formation. In summary, the disease‐associated sequence variation of Sap2 enhances pathogenicity by complement evasion and M2‐like phenotype switching, promoting a more efficient immunosuppressed microenvironment.

Candida albicans Biofilm-Derived Extracellular Vesicles Are Involved in the Tolerance to Caspofungin, Biofilm Detachment, and Fungal Proteolytic Activity

“…The highest activity affecting biofilm stability was demonstrated by Sap2, Sap9, and Sap10. Sap2 is the major aspartic proteinase of broad substrate specificity and is secreted extracellularly by C. albicans, being involved in nutrient acquisition and associated with fungal virulence-host invasion, tissue damage, and immune evasion [27,56,57]. Although the optimum activity of Sap2 is at acidic pH, research presented by Lin et al [57] showed that this proteinase might also be active at pH 7.…”

Secreted Aspartic Proteinases: Key Factors in Candida Infections and Host-Pathogen Interactions

“…As for C. parapsilosis, Sapp2 exhibits a quite narrow substrate specificity and lower catalytic activity than Sapp1 [47]. Moreover, in the case of C. albicans Saps, pH within the range of 3.0-5.0 was indicated as optimal for their proteolytic activity [44]; however, these enzymes are also active at a pH close to neutral, which significantly expands their potential range of action [44,48]. C. tropicalis Sapt2 and Sapt3 had a pH optimum of 5.0, while the optimal pH for Sapt1 activity was assigned to 3.5 [24].…”

“…Additionally, Sap2 can also interfere with CR3 and CR4 receptor expression in macrophages [138]. Recently, clinical isolates of C. albicans have been analyzed that displayed a new strategy to evade the host immune system [48]. The exchange of the amino acid at position 273 in Sap2 from valine to leucine resulted in escalated proteolytic activity of Sap2273L compared to Sap2273V, suggesting an increased ability of C. albicans to evade the complement response and, consequently, an increase in pathogenicity [48].…”

“…Recently, clinical isolates of C. albicans have been analyzed that displayed a new strategy to evade the host immune system [48]. The exchange of the amino acid at position 273 in Sap2 from valine to leucine resulted in escalated proteolytic activity of Sap2273L compared to Sap2273V, suggesting an increased ability of C. albicans to evade the complement response and, consequently, an increase in pathogenicity [48]. In the case of C. parapsilosis, Sapp1 and Sapp2 cleave complement proteins, including C4b, C3b, and FH [19].…”

Immunosuppressive microvesicles-mimetic derived from tolerant dendritic cells to target T-lymphocytes for inflammation diseases therapy

“…The conditions are characterized by systemic dysregulation of inflammatory and excessive immune responses [ 1 , 2 ]. Immunotherapy based on suppression of pro-inflammatory peripheral immune cells (neutrophils, macrophages and T lymphocytes) has been proven effective in various treatments of inflammatory diseases [ 3 , 4 ]. Tolerant dendritic cells (DC) play a critical role in immune suppression therapy [ 5 ] through various mechanisms, including depletion of auto-reactive T cells [ 6 ], promotion of regulatory T cells (Treg) [ 7 , 8 ] and expression of inhibitory molecules [ 9 , 10 ].…”