Blocking Serum Amyloid-P Component from Binding to Macrophages and Augmenting Fungal Functional Amyloid Increases Macrophage Phagocytosis of Candida albicans

Candida-macrophage interactions are important immune defense responses associated with disseminated and deep-seated candidiasis in humans. Cells of Candida spp. express functional amyloids on their surfaces during the pathogenesis of disseminated candidiasis. These amyloids become decorated with serum amyloid P-component (SAP) that binds to Candida cells and macrophages and downregulates the cellular and cytokine response to the fungi. In this report, further characterization of the interactions of SAP and fungal functional amyloid are demonstrated. Blocking the binding of SAP to macrophage FcγR1 receptors increases phagocytosis of yeast cells; seeding a pro-amyloid-forming peptide on the yeast cell surface also increases phagocytosis of yeasts by macrophages; and, lastly, miridesap, a small palindromic molecule, prevents binding of SAP to yeasts and removes SAP that is bound to C. albicans thus, potentially increasing phagocytosis of yeasts by macrophages. Some, or all, of these interventions may be useful in boosting the host immune response to disseminated candidiasis. © 2022 by the authors.Open access journalThis item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at [email protected]

The Paradoxical Effects of Serum Amyloid-P Component on Disseminated Candidiasis

Serum amyloid P component (SAP) may play an important role in human fungal diseases. SAP binds to functional amyloid on the fungal surface and masks fungi from host immune processes, skewing the macrophage population from the pro-inflammatory M1 to the quiescent M2 type. We assessed the role of SAP in a murine model of disseminated candidiasis. Mice were injected with human SAP subcutaneously (SQ) followed by intravenous injection of Candida albicans. Male, BALBcJ mice were administered 2 mg human SAP or the homologous human pro-inflammatory pentraxin CRP, SQ on day −1 followed by 1 mg on days 0 thru 4; yeast cells were administered intravenously on day 0. Mice not receiving a pentraxin were morbid on day 1, surviving 4–7 days. Mice administered SAP survived longer than mice receiving yeast cells alone (p < 0.022), although all mice died. Mice given CRP died faster than mice receiving yeast cells alone (p < 0.017). Miridesap is a molecule that avidly binds SAP, following which the complex is broken down by the liver. Miridesap administered in the drinking water removed SAP from the serum and yeast cells and significantly prolonged the life of mice (p < 0.020). Some were “cured” of candidiasis. SAP administered early in the septic process provided short-lived benefit to mice, probably by blunting cytokine secretion associated with disseminated candidiasis. The most important finding was that removal of SAP with miridesap led to prolonged survival by removing SAP and preventing its dampening effects on the host immune response. © 2022 by the authors.Open access journalThis item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at [email protected]

Quantifying the forces driving cell-cell adhesion in a fungal pathogen

Owing to its ability to form biofilms on implanted medical devices, the fungal pathogen Candida albicans causes frequent infections in humans. A hallmark of C. albicans biofilms is the presence of two types of cells, budding yeast cells and growing hyphae, which are bound together and embedded in extracellular matrix material. Although cell-cell adhesion is critical to biofilm formation, architecture, and cohesion, we know little about the fundamental forces behind this interaction. Here, we use single-cell force spectroscopy to quantify the forces engaged in yeast-hyphae adhesion, focusing on the role of Als (agglutinin-like sequence) proteins as prototypes of cell adhesion molecules. We show that adhesion between individual yeast and hyphal cells involves strong, short-range cohesive interactions (1.1 ± 0.2 nN; 86 ± 33 nm) and weak, long-range tether interactions (0.4 ± 0.2 nN; 234 ± 81 nm). Control experiments demonstrate that these interactions originate from cell surface proteins that are specific to C. albicans. Using mutant strains deficient for Als expression, we find that Als3 proteins, primarily expressed on the germ tube, play a key role in establishing strong cohesive adhesion. We suggest a model in which cohesive adhesion during biofilm formation originates from tight hydrophobic interactions between Als tandem repeat domains on adjacent cells. When subjected to force, the two interacting cell surfaces detach, but the cell bodies remain tethered through macromolecular extensions. Our results represent the first direct, noninvasive measurement of adhesion forces between interacting fungal cells and provide novel insights into the molecular origin of the cohesive strength of fungal biofilms. © 2013 American Chemical Society

Single-cell force spectroscopy of the medically important Staphylococcus epidermidis-Candida albicans interaction

Despite the clinical importance of bacterial-fungal interactions, their molecular details are poorly understood. A hallmark of such medically important interspecies associations is the interaction between the two nosocomial pathogens Staphylococcus aureus and Candida albicans, which can lead to mixed biofilm-associated infections with enhanced antibiotic resistance. Here, we use single-cell force spectroscopy (SCFS) to quantify the forces engaged in bacterial-fungal co-adhesion, focusing on the poorly investigated S. epidermidis-C. albicans interaction. Force curves recorded between single bacterial and fungal germ tubes showed large adhesion forces (∼5 nN) with extended rupture lengths (up to 500 nm). By contrast, bacteria poorly adhered to yeast cells, emphasizing the important role of the yeast-to-hyphae transition in mediating adhesion to bacterial cells. Analysis of mutant strains altered in cell wall composition allowed us to distinguish the main fungal components involved in adhesion, i.e. Als proteins and O-mannosylations. We suggest that the measured co-adhesion forces are involved in the formation of mixed biofilms, thus possibly as well in promoting polymicrobial infections. In the future, we anticipate that this SCFS platform will be used in nanomedicine to decipher the molecular mechanisms of a wide variety of pathogen-pathogen interactions and may help in designing novel anti-adhesion agents. © 2013 The Royal Society of Chemistry