Insight into Virulence and Mechanisms of Amphotericin B Resistance in the Candida haemulonii Complex
Abstract
:1. Introduction
2. Virulence Factors
2.1. Hydrolytic Enzymes
2.2. Extracellular Vesicles
2.3. Phenotypic Switching and Filamentation
2.4. Cell Aggregation
2.5. Surface Interaction Properties
2.6. Biofilm Formation
2.7. Stress Responses
2.8. Immune Evasion
3. Mechanisms of Action of Amphotericin B
3.1. Polyene–Ergosterol Interactions
3.2. Pore Formation
3.3. Surface Adsorption and Sterol Sponging Activity
3.4. Oxidative Damage
3.5. Metabolic Alterations
3.6. Formation of Ion Channels
4. Mechanisms Leading to Amphotericin B Resistance
4.1. Alterations in the Membrane Sterol Composition
4.2. Membrane Permeability
4.3. Alterations in the Accumulation of Reactive Oxidative Species
4.4. Altered Metabolic Status
4.5. Altered Iron Homoeostasis
5. Conclusions
Author Contributions
Funding
Conflicts of Interest
References
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Virulence Factors | Feature | Possible Related Genes * | Reference |
---|---|---|---|
Hydrolytic Enzymes | The capacity of hydrolytic enzymes to break down extracellular matrix proteins allows them to dismantle host barriers during infection, supplying growth nutrients and promoting infiltration and colonization of host tissues. | SAP, LIP5, LIP 6, LIP7, LIP8, SAP1, SAP2, SAP1 SAP3, SAP4, SAP5, PLB1, PLB2, PLB3 | [35] |
Extracellular vesicles (EVs) | EVs facilitate cell-to-cell communication, which mediates interactions between host and pathogen. They modulate the activation of innate immune responses, such as triggering immune reactions in effector cells like macrophages and neutrophils, influencing phagocytosis, altering macrophage orientation towards M1 or M2, elevating chemokine and cytokine concentrations, and boosting reactive oxygen species production. | NOX2 | [36] |
Phenotypic switching and filamentation | Different cell types exhibit different reactions to high temperatures, patterns of gene expression, tolerances to CuSO4, activities of secreted aspartyl proteases, and levels of virulence. Consequently, shifts among the three known phenotypes (white, pink, and filament cells) might allow C. haemulonii to swiftly adjust, endure, and prosper in specific host environments, thus enhancing its virulence. | UME6, ACO2, KGD2, IDP2, MDH1-1, HGT7, HGT17, HGT18, HGT19, CDC11, HGC1, AGA1, SAP3, SAP9, OFI1, PHO84, PHO89, TSA1, GZF3, IDH2, CPH1, HGC1, NRG1, TUP1 | [35,37] |
Cell aggregation | Aggregation phenotypes associated with abnormal cell division may play a role in helping fungi evade host immune defenses. | No genes | |
Surface interaction properties | The capacity to stick to both non-living and living surfaces influences exposure in clinical settings (e.g., via medical devices) and propensity of cells to infiltrate host tissues. | ALS1, ALS5, ECM33, IFF4, INT1, MP65, MNT1 | [35,38,39] |
Biofilm formation | Biofilms are characterized by an intricate network among microorganisms, with the biotic/non-biotic exterior being encapsulated by a self-generated extracellular matrix, which consists mainly of proteins, polysaccharides, lipids, nucleic acids, minerals, and water. Biofilms protect against external stressors, such as host immune responses and drugs, and also enhance the virulence of Candida spp., including C. haemulonii. | IFF4, BCR1, BRG1, EFG1, HSP90, NDT80, ROB1, CSR1 | [35,40] |
Stress responses | The genomes of C. haemulonii strains include direct homologs of heat resistance genes, such as those encoding heat shock proteins Hsp60, Hsp70, Hsp90, and Hsp104. HSP90 plays a key role in the morphogenesis, virulence, and azole drug tolerance of C. auris. The specific role of genes encoding heat shock proteins in the pathogenicity of C. haemulonii remains to be investigated. | HSP60, HSP104, SSA1/HSP70, HSP90 | [35] |
Immune evasion | C. haemulonii complex can employ a variety of strategies to avoid immune responses, including the creation of biofilms, synthesis of proteases, alteration of morphology, and synthesis of some specific proteins, as well as a number of other undiscovered mechanisms. | HGT1, MSB2, PRA1 | [35] |
Mechanisms | Feature | Reference |
---|---|---|
Alterations in the membrane sterol composition | The biosynthesis of ergosterol, the main sterol of the fungal cell membrane, can be disrupted by genetic mutations, thus leading to decreased susceptibility to amphotericin B (AMB) at the price of increased tolerance of external stresses, such as high temperatures, oxidative stress, and neutrophil attack. Pre-exposure to azoles can inhibit lanosterol 14-α-sterol demethylase, decreasing the production of the AMB target ergosterol. This process results in the build-up of harmful sterols within the membrane and alters membrane function. | [96,108,113,114] |
Membrane permeability | Pore formation following interaction with ergosterol is a key mechanism underlying AMB activity. Accordingly, differences in cell membrane permeability can influence AMB efficacy in different fungal isolates. | [115] |
Alterations in the accumulation of reactive oxidative species (ROS) | C. haemulonii can tolerate high concentrations of oxidative agents compared to other non-albicans Candida species, which may correlate with its elevated activity of ROS detoxification enzymes. | [106] |
Altered metabolic status | C. haemulonii species rely more on sugar fermentation rather than aerobic respiration, thereby decreasing the degree of intracellular ROS elevation. | [91] |
Altered iron homoeostasis | In Candida spp. that are similar to C. haemulonii complex spp., disrupted iron homeostasis leads to changes in membrane sterol composition, increased membrane permeability, and decreased ROS levels that may influence AMB resistance. | [116] |
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Huang, Y.; Su, Y.; Chen, X.; Xiao, M.; Xu, Y. Insight into Virulence and Mechanisms of Amphotericin B Resistance in the Candida haemulonii Complex. J. Fungi 2024, 10, 615. https://doi.org/10.3390/jof10090615
Huang Y, Su Y, Chen X, Xiao M, Xu Y. Insight into Virulence and Mechanisms of Amphotericin B Resistance in the Candida haemulonii Complex. Journal of Fungi. 2024; 10(9):615. https://doi.org/10.3390/jof10090615
Chicago/Turabian StyleHuang, Yuyan, Yanyu Su, Xinfei Chen, Meng Xiao, and Yingchun Xu. 2024. "Insight into Virulence and Mechanisms of Amphotericin B Resistance in the Candida haemulonii Complex" Journal of Fungi 10, no. 9: 615. https://doi.org/10.3390/jof10090615