Cyclosporine Affects the Main Virulence Factors of Cryptococcus neoformans In Vitro

Abstract

This study aimed to investigate the effects of cyclosporine on the morphology, cell wall structure, and secretion characteristics of Cryptococcus neoformans. The minimum inhibitory concentration (MIC) of cyclosporine was found to be 2 µM (2.4 µg/mL) for the H99 strain. Yeast cells treated with cyclosporine at half the MIC showed altered morphology, including irregular shapes and elongated projections, without an effect on cell metabolism. Cyclosporine treatment resulted in an 18-fold increase in chitin and an 8-fold increase in lipid bodies, demonstrating changes in the fungal cell wall structure. Cyclosporine also reduced cell body and polysaccharide capsule diameters, with a significant reduction in urease secretion in C. neoformans cultures. Additionally, the study showed that cyclosporine increased the viscosity of secreted polysaccharides and reduced the electronegativity and conductance of cells. The findings suggest that cyclosporine has significant effects on C. neoformans morphology, cell wall structure, and secretion, which could have implications for the development of new antifungal agents.

Natural compounds from freshwater mussels disrupt fungal virulence determinants and influence fluconazole susceptibility in the presence of macrophages in Cryptococcus neoformans

“…Inhibition of these enzymes has been widely employed by drugs like cyclosporin, a natural compound used to immunosuppress and treat multiple human diseases ( 70 , 71 ). Very recently, cyclosporin was found to have various effects on virulence and cell morphology in C. neoformans, including the cell wall and the polysaccharide capsule ( 11 ).…”

“…Although this effect was not enough to impair C. neoformans ability to tolerate osmotic stress, it may impact cell wall morphology, which is essential for capsule formation ( 73 , 74 ). Similarly, calcineurins are calcium-binding proteins involved in capsule production, and their inhibition is known to cause cell wall impairment ( 11 ). Here, we also observed seven calcium-binding proteins that may impact the role of calcineurin and, eventually, capsule production ( 8 ).…”

“…However, the emergence of resistant strains with higher tolerance to this drug is a serious threat to current treatments, especially in less-developed countries. Our proteomics profiling detected four calcium-binding proteins that may impair secretory mechanisms used by C. neoformans to form extracellular structures, such as the capsule or the cell wall, and potentially impacting drug resistance ( 11 , 90 ). Another possible mechanism may be membrane destabilization by extracts from the L. costata mantle, which can also affect the permeabilization of the cell wall and capsule ( 90 ).…”

“…One of the most important is the polysaccharide capsule, which is comprised mainly of glucuronoxylomannan (GXM) and protects the fungus from desiccation within the natural environment and the phagocytic action of the host immune system ( 10 ). Inhibiting capsule formation or disrupting its structure increases the vulnerability of the fungus to an immune attack and enhances the efficacy of antifungal treatments ( 9 , 11 ). Melanin is another critical virulence determinant, a dark pigment that protects against environmental stresses and antifungal drugs ( 12 ).…”

Insights and Perspectives on the Role of Proteostasis and Heat Shock Proteins in Fungal Infections

“…FK506 has an additive effect on Hsp90 repression via Geldanamycin; however, the immunosuppressive properties of this calcineurin inhibitor outweigh its antifungal action in vivo [ 16 , 184 ]. Cyclosporine A might be a more suitable inhibitor in this case since it has significant antifungal effects against C. neoformans and has demonstrated synergistic properties with Amphotericin B [ 185 , 186 ].…”