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Simultaneous Nanoscale Imaging of Chemical and Architectural Heterogeneity on Yeast Cell Wall Particles.

ABSTRACT: Particles extracted from yeast cell walls are naturally occurring immunomodulators with significant therapeutic applications. Their biological function has been thought to be a consequence of the overall chemical composition. In contrast, here we achieve direct nanoscale visualization of the compositional and structural heterogeneity of yeast cell wall particles and demonstrate that such nanoscale heterogeneity directly influences the receptor function of immune cells. By combining peak force infrared (PFIR) microscopy with super-resolution fluorescence microscopy, we achieve simultaneous chemical, topographical, and mechanical mapping of cell wall particles extracted from the yeast Saccharomyces cerevisiae with ≈6 nm resolution. We show that polysaccharides (β-glucan and chitin) and proteins are organized in specific nonuniform structures, and their heterogeneous spatial organization leads to heterogeneous recruitment of receptors on immune cell membranes. Our findings indicate that the biological function of yeast cell wall particles depends on not only their overall composition but also the nanoscale distribution of the different cell wall components.

SUBMITTER: Li W

PROVIDER: S-EPMC7882198 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Visceral leishmaniasis, caused by Leishmania infantum, is a neglected tropical disease, to which efforts in the innovation of effective and affordable treatments remain limited, despite the rising incidence in several regions of the world. In this work, the antileishmanial effects of sugiol were investigated in vitro. This compound was isolated from the bark of Cupressus lusitanica and showed promising activity against L. infantum. In spite of the positive results, it is known that the compound is a poorly water-soluble diterpene molecule, which hinders further investigation, especially in preclinical animal studies. Thus, in an alternative delivery method, sugiol was entrapped in glucan-rich particles obtained from Saccharomyces cerevisiae yeast cell walls (YCWPs). To evaluate the activity of sugiol, the experiments were divided into two parts: (i) the in vitro investigation of antileishmanial activity of free sugiol against L. infantum promastigotes after 24, 48, and 72 h of treatment and (ii) the evaluation of antileishmanial activity of sugiol entrapped in glucan-rich particles against intracellular L. infantum amastigotes. Free sugiol induced the cell-death process in promastigotes, which was triggered by enhancing cytosolic calcium level and promoting the autophagy up to the first 24 h. Over time, the presence of autophagic vacuoles became rarer, especially after treatment with lower concentrations of sugiol, but other cellular events intensified, like ROS production, cell shrinkage, and phosphatidylserine exposure. Hyperpolarization of mitochondrial membrane potential was found at 72 h, induced by the mitochondria calcium uptake, causing an increase in ROS production and lipid peroxidation as a consequence. These events resulted in the cell death of promastigotes by secondary necrosis. Sugiol entrapped in glucan-rich particles was specifically recognized by dectin-1 receptor on the plasma membrane of macrophages, the main host cell of Leishmania spp. Electron micrographs revealed particles containing sugiol within the infected macrophages and these particles were active against the intracellular L. infantum amastigotes without affecting the host cell. Therefore, the YCWPs act like a Trojan horse to successfully deliver sugiol into the macrophage, presenting an interesting strategy to deliver water-insoluble drugs to parasitized cells.

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Simultaneous Nanoscale Imaging of Chemical and Architectural Heterogeneity on Yeast Cell Wall Particles.

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