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

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.