| Summary: | Sporotrichosis is a human and animal fungal infection distributed worldwide that is caused by the thermodimorphic species of the <i>Sporothrix</i> pathogenic clade, which includes <i>Sporothrix brasiliensis</i>, <i>Sporothrix schenckii</i>, and <i>Sporothrix globosa</i>. The cell wall composition and the immune response against the <i>Sporothrix</i> species have been studied mainly in <i>S. brasiliensis</i> and <i>S. schenckii</i>, whilst little is known about the <i>S. globosa</i> cell wall and the immune response that its components trigger. Therefore, in this study, we aimed to analyze the cell wall composition of <i>S. globosa</i> in three morphologies (germlings, conidia, and yeast-like cells) and the differences in cytokine production when human peripheral blood mononuclear cells (PBMCs) interact with these morphotypes, using <i>S. schenckii</i> and <i>S. brasiliensis</i> as a comparison. We found that <i>S. globosa</i> conidia and yeast-like cells have a higher cell wall chitin content, while all three morphologies have a higher β-1,3-glucan content, which was found most exposed at the cell surface when compared to <i>S. schenckii</i> and <i>S. brasiliensis</i>. In addition, <i>S. globosa</i> has lower levels of mannose- and rhamnose-based glycoconjugates, as well as of <i>N</i>- and <i>O</i>-linked glycans, indicating that this fungal cell wall has species-specific proportions and organization of its components. When interacting with PBMCs, <i>S. brasiliensis</i> and <i>S. globosa</i> showed a similar cytokine stimulation profile, but with a higher stimulation of IL-10 by <i>S. globosa</i>. Additionally, when the inner cell wall components of <i>S. globosa</i> were exposed at the surface or <i>N</i>- and <i>O</i>-glycans were removed, the cytokine production profile of this species in its three morphotypes did not significantly change, contrasting with the <i>S. schenckii</i> and <i>S. brasiliensis</i> species that showed different cytokine profiles depending on the treatment applied to the walls. In addition, it was found that the anti-inflammatory response stimulated by <i>S. globosa</i> was dependent on the activation of dectin-1, mannose receptor, and TLR2, but not TLR4. All of these results indicate that the cell wall composition and structure of the three <i>Sporothrix</i> species in the three morphologies are different, affecting their interaction with human PBMCs and generating species-specific cytokine profiles.
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