The fungal cell wall is located outside the plasma membrane and is the cell compartment that mediates all the relationships of the cell with the environment. It protects the contents of the cell, gives rigidity and defines the cellular structure. The cell wall is a skeleton with high plasticity that protects the cell from different stresses, among which osmotic changes stand out. The cell wall allows interaction with the external environment since some of its proteins are adhesins and receptors. Since, some components have a high immunogenic capacity, certain wall components can drive the host’s immune response to promote fungus growth and dissemination. The cell wall is a characteristic structure of fungi and is composed mainly of glucans, chitin and glycoproteins. As the components of the fungal cell wall are not present in humans, this structure is an excellent target for antifungal therapy. In this article, we review recent data on the composition and synthesis, influence of the components of the cell wall in fungi-host interaction and the role as a target for the next generation of antifungal drugs in yeasts (Candida and Cryptococcus) and filamentous fungi (Aspergillus).

Due to its location, the fungal cell wall is the compartment that allows the interaction with the environment and/or the host, playing an important role during infection as well as in different biological functions such as cell morphology, cell permeability and protection against stress. All these processes involve the activation of signaling pathways within the cell. The cell wall integrity (CWI) pathway is the main route responsible for maintaining the functionality and proper structure of the cell wall. This pathway is highly conserved in the fungal kingdom and has been extensively characterized in Saccharomyces cerevisiae. However, there are still many unknown aspects of this pathway in the pathogenic fungi, such as Cryptococcus neoformans. This yeast is of particular interest because it is found in the environment, but can also behave as pathogen in multiple organisms, including vertebrates and invertebrates, so it has to adapt to multiple factors to survive in multiple niches. In this review, we summarize the components of the CWI pathway in C. neoformans as well as its involvement in different aspects such as virulence factors, morphological changes, and its role as target for antifungal therapies among others.

Cryptococcus neoformans is a pathogenic yeast that can form Titan cells in the lungs, which are fungal cells of abnormally large size. The factors that regulate Titan cell formation in vivo are still unknown, although an increased proportion of these fungal cells of infected mice correlates with induction of Th2-type responses. Here, we focused on the role played by the cytokine IL-17 in the formation of cryptococcal Titan cells using Il17a^−/− knockout mice. We found that after 9 days of infection, there was a lower proportion of Titan cells in Il17a^−/− mice compared to the fungal cells found in wild-type animals. Dissemination to the brain occurred earlier in Il17a^−/− mice, which correlated with the lower proportion of Titan cells in the lungs. Furthermore, knockout-infected mice increased brain size more than WT mice. We also determined the profile of cytokines accumulated in the brain, and we found significant differences between both mouse strains. We found that in Il17a^−/−, there was a modest increase in the concentrations of the Th1 cytokine TNF-α. To validate if the increase in this cytokine had any role in cryptococcal morphogenesis, we injected wild-type mice with TNF-α t and observed that fungal cell size was significantly reduced in mice treated with this cytokine. Our results suggest a compensatory production of cytokines in Il17a^−/− mice that influences both cryptococcal morphology and dissemination.

Human IgM was previously shown to inhibit Titan-like cell formation of Cryptococcus neoformans , whereas IgG did not. Here, we conducted an in-depth analysis of the effect of normal human IgA on C. neoformans biology (strain H99) and compared it to that of IgG and IgM. We found that like IgM, IgA affected H99 cell size and morphology. The total size of cells cultured with IgA was significantly smaller at 24 h than cells cultured with IgM and IgG and comparable to IgM but smaller than IgG at 72 h. We also examined extracellular vesicle (EV) production and found that it was significantly reduced in cells cultured with IgA than the control, but the EVs were larger. To further probe the effect of IgA on H99, we performed expression profiling by RNAseq of H99 cells cultured with each immunoglobulin isotype and compared the results with IgA to those with IgM, IgG, and a control (PBS). These comparisons showed that cells cultured with IgA overexpressed genes related to cell rescue, defense, virulence, energy conservation, adapation to stress with CNAG_00735 (aldehyde dehydrogenase family seven member A1) being the most overexpressed, and repressed some genes related to vesicular transport, including CNAG_04306 (vesicle transporter SFT2B) and CNG_00063 (histone H3). Collectively, our findings suggest that the effects of IgA on cryptococcal biology deserve further investigation, as they reveal new insights into human host– C. neoformans interaction, which suggest that antibody responses may affect gene expression in C. neoformans . IMPORTANCE: Profound CD4 T cell deficiency is associated with the development of cryptococcosis in HIV-infected individuals. However, perturbations in antibody immunity, including reduced levels of plasma IgA and IgM, have also been associated with cryptococcal disease status. While IgM has been studied in some detail, IgA has not. Here, we evaluated the effect of normal human IgA on Cryptococcus neoformans biology and morphology to expand knowledge of the role that it may play in cryptococcal pathogenesis.